The potential impact of CYP and UGT drug-metabolizing enzymes on brain target site drug exposure

Figures & data

Figure 1. The majority subcellular locations of CYPs and UGTs in brain cell. The expression of CYPs was detected on the plasma membrane, but mainly in the cytoplasmic side of ER (Zhang et al. 2016) and the inner membrane of the mitochondria (Walther et al. 1986). However, the substrate binding sites are deeply buried in the phospholipid bilayer membranes (Šrejber et al. 2018). UGTs are predominantly located on the luminal side of the ER (Ouzzine et al. 2014).

Table 1. Distribution of major CYP family DMEs in different regions and cell types in human, rat, and mouse brains rat, mouse and human CYPs that are present in several distinct brain localizations.

CYP family	Isoform	Species	Expression	Localization in brain													Cell types			Techniques	Refs.
				Cortex	Basal ganglia	Olfactory bulb	Amygdala	Hippocampus	Cerebellum	Midbrain	Medulla oblongata	Pons	Thalamus	Hypothalamus	BBB	Others	Endothelial cells	Astrocytes	Neurons
1	1A1	Human	RNA/mRNA	+	+		+	+	+	+	+	+	+	+		+		+	+	RT-PCR/FISH/Northern b/Qt RT-PCR/RNA-Seq	Dutheil et al. (2008), Dutheil et al. (2009), Ghosh et al. (2016), and Sjöstedt et al. (2020)
			Protein	+	+			+	+	+	+	+	+			+		+	+	Western b/Immunoh	Bhagwat et al. (2000), Miksys SL and Tyndale (2002), Dutheil et al. (2008), and Ghosh et al. (2016)
		Rat	mRNA	+	+	+			+	+	+			+						RT-PCR	Schilter and Omiecinski (1993)
			Protein	+					+							+				Western b	Morse et al. (1998) and Iba et al. (2003)
		Mouse	RNA/mRNA	+	+	+	+	+	+	+	+	+	+	+		+		+	+	RNA-Seq/Hyb in situ	Dey et al. (1999), Ghosh et al. (2016), and Sjöstedt et al. (2020)
			Protein	+		+									+	+		+	+	Semi-Qt RT–PCR/Western b/Immunob	Huang et al. (2000), Meyer et al. (2002), and Granberg et al. (2003)
	1A2	Human	RNA/mRNA	+	+		+	+	+	+	+	+	+	+		+		+	+	RT-PCR/RNA-Seq	Farin and Omiecinski (1993), McFadyen et al. (1998), Dutheil et al. (2008), Ghosh et al. (2016), Sjöstedt et al. (2020), and Fanni et al. (2021)
			Protein	+	+			+	+	–	+	+	+			+		+	+	Western b	Bhagwat et al. (2000), Dutheil et al. (2008), and Ghosh et al. (2016)
		Rat	mRNA	–	+	+		–	–	+	+	+	+	+				+	+	RT-PCR/Qt-PCR	Schilter and Omiecinski (1993), Stamou et al. (2014), and Ghosh et al. (2016)
			Protein	+	+			+	+	+	+	+	+	+				+	+	Western b	Morse et al. (1998), Iba et al. (2003), and Ghosh et al. (2016)
		Mouse	RNA/mRNA		+	+	+	+	+	+	+	+	+	+		+				Hyb in situ	Dey et al. (1999) and Sjöstedt et al. (2020)
	1B1	Human	RNA/mRNA	+	+		+	+	+	+	+	+	+	+		+		+		RT-PCR/Northern b/RNA-Seq	McFadyen et al. (1998), Rieder CR et al. (1998), Dutheil et al. (2008), Sjöstedt et al. (2020), and Fanni et al. (2021)
			Protein	+	+										+		+	+	+	Immunob/Immunoh/Western b	Murray et al. (1997), Rieder CRM et al. (2000), Muskhelishvili et al. (2001), Dauchy et al. (2008), Ghosh et al. (2016), and Fanni et al. (2021)
		Rat	mRNA														+	+		RT-PCR	Granberg et al. (2003) and Yu X et al. (2019)
			Protein														+	+		Immunoh/Western b	Granberg et al. (2003) and Yu X et al. (2019)
		Mouse	RNA	+	+		+	+	+	+	+	+	+	+		+				RNA-Seq/Hyb in situ	Sjöstedt et al. (2020)
			Protein												+		+			Immunoh	Granberg et al. (2003)
2	2A1	Rat	mRNA	+		+		+	+	+	+	+								RT-PCR	Oguro et al. (2021)
	2A3	Rat	mRNA	+					+											RT-PCR	Oguro et al. (2021)
	2A6	Human	RNA	+	+		+	+	+	+	+	+	+	+		+				RNA-Seq	Sjöstedt et al. (2020)
	2B1	Rat	mRNA	+	+	+		–	+									+	+	RT-PCR/Qt-PCR	Volk et al. (1995), Stamou et al. (2014), and Ghosh et al. (2016)
			Protein	+	+	+		+				+	+					+	+	Immunocyto/Hybe in situ/Northern b/Western b	Volk et al. (1995), Miksys S, Hoffmann, et al. (2000), and Ghosh et al. (2016)
	2B2	Rat	mRNA	+				–	+											RT-PCR/Qt-PCR	Schilter and Omiecinski (1993) and Stamou et al. (2014)
	2B6	Human	RNA	+	+		+	+	+	+	+	+	+	+		+				RNA-Seq	Sjöstedt et al. (2020)
			Protein	+	+		+	+	+	+	+	+			+	+		+	+	Western b/Immunoh	Miksys S et al. (2003), Dutheil et al. (2008), Ghosh et al. (2016), and Fanni et al. (2021)
	2B10	Mouse	Protein					+											+	Western b/Immunoe	Thuerl et al. (1997) and Ghosh et al. (2016)
	2C6	Rat	Protein		–															Immunoh	Riedl et al. (2000)
	2C8	Human	RNA	+	+		+	+	+	+	+	+	+	+		+				RNA-Seq	Sjöstedt et al. (2020)
	2C9	Human	Protein	+	+		+	+	+										+	Western b	Booth Depaz et al. (2015) and Fanni et al. (2021)
			RNA/mRNA	–	–		–	–	+	–	+	+	–	–		+		+		RNA-Seq	Ghosh et al. (2016) and Sjöstedt et al. (2020)
	2C11	Rat	mRNA	+		+		+	+	+	+	+						+		RT-PCR	Alkayed et al. (1996), Ghosh et al. (2016), Navarro-Mabarak et al. (2020), and Oguro et al. (2021)
			Protein	+	–															Western b/Immunoh	Riedl et al. (2000) and Navarro-Mabarak et al. (2020)
	2C18	Human	RNA	+	+		–	+	+	–	+	+	+	–		+				RNA-Seq	Sjöstedt et al. (2020)
	2C19	Human	RNA	+	+		+	+	+	–	+	+	–	–		+				RNA-Seq	Sjöstedt et al. (2020)
			Protein	+	+		+	+	+										+	Western b	Booth Depaz et al. (2015) and Fanni et al. (2021)
	2C29	Mouse	Protein												+	+		+		Immunocyto	Volk et al. (1995), Meyer et al. (2001), and Ghosh et al. (2016)
	2D1	Rat	mRNA	+	+	+		+	+		+	+							+	RT-PCR	Miksys S, Rao, et al. (2000) and Ghosh et al. (2016)
			Protein							+									+	Southern b/Western b/Immunoh	Miksys S, Rao, et al. (2000), Gilbert et al. (2003), and Ghosh et al. (2016)
	2D2	Rat	Protein							+										Immunoh	Gilbert et al. (2003)
	2D3	Rat	Protein							+										Immunoh	Gilbert et al. (2003)
	2D4	Rat	mRNA		+				+		+	+								Immunoh	Funae et al. (2003)
			Protein	–	–	+		–	+	+			–	+		+			+	Immunoh/Hyb in situ	Riedl et al. (1999), Gilbert et al. (2003), and Ghosh et al. (2016)
	2D5	Rat	Protein	+	+	+		+		+			+	+		+				Immunoh/immunocyto	Riedl et al. (1999) and Gilbert et al. (2003)
	2D6	Human	RNA/mRNA	+	+		+	+	+	+	–	+	+	–		+			+	Hyb in situ/RT-PCR/FISH/Southern b/RNA-Seq	McFadyen et al. (1998), Dutheil et al. (2008), Ghosh et al. (2016), and Sjöstedt et al. (2020)
			Protein	+	+		+	+	+	+	+		+	+					+	Western b	Siegle et al. (2001), Chinta et al. (2002), Ghosh et al. (2016), and Fanni et al. (2021)
	2D22	Mouse	Protein		+															Immunoh/Western b	Singh et al. (2009)
	2E1	Human	Protein	+	+		+	+	+	+	+	+	+		+	+	+	+	+	Western b/Immunoh/Immunob	Bhagwat et al. (2000), Dutheil et al. (2008), Toselli et al. (2015), and Ghosh et al. (2016)
			RNA/mRNA	+	+		+	+	+	+	+	+	+	+		+			+	RT-PCR/FISH/Northern b/RNA-Seq	Dutheil et al. (2008), Ghosh et al. (2016), Sjöstedt et al. (2020), and Fanni et al. (2021)
		Rat	mRNA	+		+		+	+	+	+	+								RT-PCR	Oguro et al. (2021)
		Mouse	RNA/mRNA	+	+	+	–	+	+	+	+	–	+	+		+			+	RNA-Seq/Hyb in situ	Ghosh et al. (2016), Sjöstedt et al. (2020), and Fanni et al. (2021)
			Protein	+	+			+	+		+	+			+		+	+	+	Western b/Immunoh	Boussadia et al. (2014) and Fanni et al. (2021)
	2J2	Human	RNA/mRNA	+	+		+	+	+	+	+	+	+	+		+	+	+		RNA-Seq	Ghosh et al. (2016), Liu M et al. (2017), and Sjöstedt et al. (2020)
			Protein	+			+													Immunob	Toselli et al. (2015)
	2J3	Rat	mRNA															+		Qt RT-PCR	Navarro-Mabarak et al. (2020)
			Protein	+																Western b	Navarro-Mabarak et al. (2020)
	2J9	Mouse	mRNA	+				+	+	+	+	+							+	Northern b	Ghosh et al. (2016)
3	3A1	Rat	mRNA	+		+		+	+	+	+	+		+						RT-PCR	Woodland et al. (2008)
	3A2	Rat	Protein	+					+											Immunob/CAA	Vences-Mejía et al. (2006, 2012)
	3A4	Human	RNA/mRNA	+	+		+	+	–	–	–	–	+	–		+	+		+	RT-PCR/RNA-Seq	Dutheil et al. (2008), Woodland et al. (2008), Ghosh et al. (2016), and Sjöstedt et al. (2020)
			Protein	+									+				+		+	CCA	Voirol et al. (2000) and Ghosh et al. (2016)
	3A5	Human	RNA/mRNA	+	+		+	+	–	+	–	–	–	–		+				RT-PCR/RNA-Seq	Dutheil et al. (2008), Woodland et al. (2008), and Sjöstedt et al. (2020)
			Protein	–	–			–	–	–	–	–				+				Western b	Murray et al. (1995)
	3A7	Human	RNA	+	–		–	–	–	–	+	–	–	+		–				RNA-Seq	Sjöstedt et al. (2020)
	3A9	Rat	mRNA						+										+	Northern b	Wang H et al. (1996)
	3A11	Mouse	Protein			+		+	+					+			+		+	Immunob	Hagemeyer et al. (2003) and Woodland et al. (2008)
	3A13	Mouse	Protein			+		+						+			+		+	Immunob	Hagemeyer et al. (2003) and Woodland et al. (2008)
	3A43	Human	RNA	+	+		–	+	–	–	–	–	–	–		+				RNA-Seq	Sjöstedt et al. (2020)

CAA: catalytic activities; FISH: fluorescence in situ hybridization; Hyb in situ: hybridization in situ; Immunob: immunoblotting with antibodies; Immunocyto: immunocytochemistry; Immunoe: immunoelectron microscopy; Immunoh: immunohistochemistry; Northern b: Northern blot; RNA d.b. : RNA dot blot; RNA-Seq: RNA-sequencing; RT-PCR: reverse transcriptase-polymerase chain reaction; Qt RT–PCR: quantitative RT-PCR; semi-Qt RT-PCR: semiquantitative RT-PCR; Southern b: Southern blot; Western b: Western blot.

Presence (+) and absence (−) of CYPs are represented according to brain localization. The expression data in some studies did not match the expression data in the Human Protein Atlas. When this was the case, we chose to trust the study-specific expression data.

Table 2. Distribution of major UGT family DMEs in different regions and cell types in human, rat, and mouse brains rat, mouse and human UGT DMEs that are present in several distinct brain localizations.

UGT super family	Isoform	Species	Expression	Localization in brain													Cell types				Techniques	Refs.
				Cortex	Basal ganglia	Olfactory bulb	Amygdala	Hippocampus	Cerebellum	Midbrain	Medulla oblongata	Pons	Thalamus	Hypothalamus	BBB	Others	Endothelial cells	Astrocytes	Neurons	Glial cell
1	1A1	Human	RNA	+	+	+	+	+	+	+	+	+	+	+		+					RNA-Seq	Kutsuno et al. (2015) and Sjöstedt et al. (2020)
		Rat	mRNA	+		+			+												RT-PCR	Shelby et al. (2003), Ouzzine et al. (2014), and Gambaro et al. (2016)
			Protein	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	+	Western b	Togna et al. (2013) and Ouzzine et al. (2014)
		Mouse	mRNA	+	+	+	+	+	+	+	+	+	+	+							RT-PCR/Qt RT-PCR	Kutsuno et al. (2015) and Sjöstedt et al. (2020)
	1A2	Rat	mRNA			+															RT-PCR	Heydel et al. (2010)
	1A3	Human	RNA	–	–		–	–	–	–	–	–	–	–		–					RNA-Seq	Sjöstedt et al. (2020)
		Rat	mRNA	+		+			+												RT-PCR	Shelby et al. (2003) and Heydel et al. (2010)
	1A4	Human	mRNA/RNA	–	–		–	–	+	–	–	–	–	–							RT-PCR/RNA-Seq	Court et al. (2012) and Sjöstedt et al. (2020)
			Protein												+		+		+		Immunob	Ouzzine et al. (2014)
	1A6	Human	mRNA/RNA	–	–		–	–	+	–	–	–	–	–	–		–	–	–		RT-PCR/RNA-Seq	King et al. (1999), Ouzzine et al. (2014), and Sjöstedt et al. (2020)
			Protein												–		–	–	–		Immunob	Ouzzine et al. (2014)
		Rat	mRNA	+		+			+						+		+	+	+		RT-PCR/Qt RT-PCR	Shelby et al. (2003), Gradinaru et al. (2009), Heydel et al. (2010), and Ouzzine et al. (2014)
			Protein												+		+	+	+	+	Immunob/Western b	Togna et al. (2013) and Ouzzine et al. (2014)
		Mouse	mRNA	+		+		+	+	+											RT-PCR/Qt RT-PCR	Kutsuno et al. (2015)
	1A7	Human	RNA	+	+		+	+	+	+	+	+	+	+		+					RNA-Seq	Sjöstedt et al. (2020)
		Rat	mRNA	+		+		+	+		+		+								RT-PCR	Sakakibara et al. (2016)
	1A8	Human	RNA	–	–		–	–	–	–	–	–	–	–		–					RNA-Seq	Sjöstedt et al. (2020)
		Rat	mRNA	+		+			+												RT-PCR	Shelby et al. (2003) and Heydel et al. (2010)
	1A9	Human	RNA	–	–		–	–	–	–	–	–	–	–		–					RNA-Seq	Sjöstedt et al. (2020)
	1A10	Human	mRNA/RNA	–	–		–	–	+	–	–	–	–	–		–					RT-PCR/RNA-Seq	Court et al. (2012) and Sjöstedt et al. (2020)
		Rat	mRNA			+															RT-PCR	Heydel et al. (2010)
2	2B1	Rat	mRNA	+		–			+												RT-PCR	Shelby et al. (2003) and Heydel et al. (2010)
			Protein																	_	Western b	Togna et al. (2013)
	2B4	Human	RNA	–	–		–	–	–	–	–	–	–	–		–					RNA-Seq	Sjöstedt et al. (2020)
	2B7	Human	mRNA/RNA	–	–		–	–	+	–	–	–	–	–		–					RT-PCR/RNA-Seq	King et al. (1999), Heydel et al. (2010), and Sjöstedt et al. (2020)
		Rat	Protein	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–	–		CCA	Suleman et al. (1993)
	2B10	Human	RNA	–	–		–	–	–	–	–	–	–	–		–					RNA-Seq	Sjöstedt et al. (2020)
	2B15	Human	RNA	–	–		–	–	–	–	–	–	–	–		–					RNA-Seq	Sjöstedt et al. (2020)
		Rat	mRNA	+		–			+												RT-PCR	Heydel et al. (2010) and Kutsuno et al. (2015)
	2B17	Human	mRNA/RNA	–	–		–	–	+	–	–	–	–	–		–					RT-PCR/RNA-Seq	Court et al. (2012) and Sjöstedt et al. (2020)

CAA: catalytic activities; FISH: fluorescence in situ hybridization; Hyb in situ: hybridization in situ; Immunob: immunoblotting with antibodies; Immunocyto: immunocytochemistry; Immunoh: immunohistochemistry; Northern b: Northern blot; RNA d.b.: RNA dot blot; RNA-Seq: RNA-sequencing; RT-PCR: reverse transcriptase–polymerase chain reaction; Qt RT-PCR: quantitative RT-PCR; Southern b: Southern blot; Western b: Western blot.

Presence (+) and absence (−) of CYPs are represented according to brain localization. The expression data in some studies did not match the expression data in the Human Protein Atlas. When this was the case, we chose to trust the study-specific expression data.

Table 3. Major CYP family DME genes in human, rat, and mouse brains.

Family	Subfamily	Human	Rat	Mouse	Ref.
CYP1	A	CYP1A1 CYP1A2	Cyp1a1 Cyp1a2	Cyp1a1 Cyp1a2	Martignoni et al. (2006), Nagai et al. (2016), and Sayers et al. (2021)
	B	CYP1B1	Cyp1b1	Cyp1b1	Martignoni et al. (2006) and Jacob et al. (2011)
CYP2	A	CYP2A6	Cyp2a1 Cyp2a3	–	Imaoka et al. (2005), Martignoni et al. (2006), Yu Y et al. (2014), Yue F et al. (2014), and Sayers et al. (2021)
	B	CYP2B6	Cyp2b1	Cyp2b10	Martignoni et al. (2006), Yue F et al. (2014), Nagai et al. (2016), and Sayers et al. (2021)
	C	CYP2C8 CYP2C9 CYP2C18 CYP2C19	Cyp2c6 Cyp2c11	Cyp2c29	Martignoni et al. (2006), Yue F et al. (2014), and Nagai et al. (2016)
	D	CYP2D6	Cyp2d1 Cyp2d2 Cyp2d3 Cyp2d4 Cyp2d5 Cyp2d18	Cyp2d22	Riedl et al. (1999), Martignoni et al. (2006), Yue F et al. (2014), and Nagai et al. (2016)
	E	CYP2E1	Cyp2e1	Cyp2e1	Martignoni et al. (2006) and Nagai et al. (2016)
	J	CYP2J2	Cyp2j3	Cyp2j9	Yu Y et al. (2014), Yue F et al. (2014), and Ghosh et al. (2016)
CYP3	A	CYP3A4 CYP3A5 CYP3A7 CYP3A43	Cyp3a1 Cyp3a2 Cyp3a9	Cyp3a11 Cyp3a13	Martignoni et al. (2006), Yu Y et al. (2014), Yue F et al. (2014), and Nagai et al. (2016)

Protein-coding genes of major CYP DMEs present in humans, rats, and mice.

Table 4. Major UGT family DME genes in human, rat, and mouse brains.

Family	Subfamily	Human	Rat	Mouse	Ref.
UGT1	A	UGT1A1 UGT1A3 UGT1A4 UGT1A6 UGT1A7 UGT1A10	Ugt1a1 Ugt1a2 Ugt1a3 Ugt1a6 Ugt1a7 Ugt1a8 Ugt1a10	Ugt1a1 Ugt1a6	Kiang et al. (2005), Nakajima et al. (2007), Jancova et al. (2010), Rowland et al. (2013), Yu Y et al. (2014), Yue F et al. (2014), Wishart et al. (2018), Meech et al. (2019), Sjöstedt et al. (2020), and Sayers et al. (2021)
UGT2	B	UGT2B7 UGT2B17	Ugt2b1 Ugt2b7 Ugt2b15	Ugt2b5

Protein-coding genes of major UGT DMEs present in humans, rats, and mice.

Table 5. Comparison of ex vivo and in vivo enzyme activity measurement methods.

Method	Substrate	Application	Key principle	Advantages	Disadvantages	Ref.
Fluorescence-based methods
FRET	Artificial substrates	Imaging enzyme activity in vivo	Fluorescence resonance energy transfer between donor and acceptor fluorophores	High sensitivity and specificity	Limited to small substrate molecules	Frommer et al. (2009)
Quenching phenomena			Fluorescence quenching upon cleavage of the substrate by the enzyme			Johansson and Cook (2003)
ISZ						Galis et al. (1994)
Protease-activated fluorogenic probes						Weissleder et al. (1999)
Activity-based fluorescent probes			Fluorescence increase upon binding to the active site of the enzyme			Kwan et al. (2011)
Differential in vivo zymography	Natural substrates	Imaging enzyme activity in vivo	Visualization of enzyme activity in tissue sections	Direct visualization of enzyme activity in tissue	Limited to specific enzymes	Vandooren et al. (2013)
Magnetic resonance-based methods
Various isotope labels	Natural substrates	Imaging enzyme activity in vivo	Detection of changes in magnetic resonance signals upon substrate cleavage by the enzyme	Non-invasive and high spatial resolution	Limited sensitivity	Kanamori and Ross (2005), Dona et al. (2016), Kanamori (2017), and Rackayova et al. (2017)
Mass spectrometry-based methods
MALDI	Artificial substrates	Imaging enzyme activity ex vivo	Detection of mass changes upon substrate cleavage by the enzyme	High sensitivity and specificity	Limited to small substrate molecules	Greis (2007) and Koehbach et al. (2016)
SALDI
NIMS
SAMDI
MALDI-LTQ-Orbitrap XL						OuYang et al. (2015)
Sampling-based methods
Microdialysis	Natural substrates	In vivo measurement of enzyme activity	Collection and quantification of diffusing components of the extracellular space (ECS)	Broad applicability, ease of coupling to separation and detection methods	Limited spatial resolution	Wang Y et al. (2009)
EO		Ex vivo measurement of enzyme activity in tissue cultures	Bulk fluid movement through electrolyte-filled conduits with charged walls	High sensitivity, measurement of enzyme activity ex vivo	Limited to tissue cultures	Wu et al. (2013)
EOPPP			Fluid flows from the bath beneath the culture, through the tissue culture, and enters the sampling capillary	Measurement of enzyme activity ex vivo		Rupert et al. (2013)

FRET: Förster (or ‘fluorescence’) resonance energy transfer; ISZ: ion-sensitive electrodes; MALDI: matrix-assisted laser desorption/ionization; SALDI: surface-assisted laser desorption/ionization; NIMS: nanostructure-initiator mass spectrometry; SAMDI: self-assembled monolayers for matrix-assisted laser desorption/ionization; MALDI-LTQ-Orbitrap XL: matrix-assisted laser desorption/ionization linear trap quadrupole Orbitrap XL; EO: electroosmotic; EOPPP: electroosmotic push-pull perfusion.

Comparison of various methods for measuring enzyme activity ex vivo and in vivo, including the substrates used, applications, and fundamental principles associated with each method.

Table 6. DMEs in human brains and corresponding CNS-active drugs as substrates.

CYP enzymes	CNS-acting drugs	Ref.
CYP1A1	Carvedilol, lorcaserin, nicotine, rifampicin, riluzole, 7,12-dimethylbenz(a) anthracene (DMBA), 7-ethoxyresorufin	Fernandes et al. (2016), Ghosh et al. (2016), and Wishart et al. (2018)
CYP1A2	Aspartame, caffeine, carvedilol, clozapine, diazepam, fluoxetine, frovatriptan, phenacetin, haloperidol, lorcaserin, palonosetron, perampanel, phenytoin, primidone, ramelteon, rasagiline, remoxipride, riluzole, ropinirole, tacrine, tasimelteon, tizanidine, zolmitriptan, 7-ethoxyresorufin	Fernandes et al. (2016), Ghosh et al. (2016), and Wishart et al. (2018)
CYP2A6	Lorcaserin, phenytoin, valproic acid	Fernandes et al. (2016) and Wishart et al. (2018)
CYP1B1	Arachidonic acid, β-naphthoflavone, nicotine, stilbene, 7,12-dimethylbenz(a)anthracene (DMBA)	Ghosh et al. (2016)
CYP2B6	Brivaracetam, bupropion, carbamazepine, chlorpyrifos, cyclophosphamide, diazepam, efavirenz, ethanol, fluoxetine, ifosfamide, ketamine, lorcaserin, malathion, meperidine, methadone, nicotine, N,N-diethyl-m-toluamide (DEET), paraquat, parathion, pentobarbital, perampanel, phenytoin, phencyclidine, propofol, sertraline, selegiline, tramadol, valproic acid	Miksys S and Tyndale (2013), Fernandes et al. (2016), Ghosh et al. (2016), and Wishart et al. (2018)
CYP2C8	Almotriptan, phenytoin, carbamazepine, celecoxib, eszopiclone, nabilone	Fernandes et al. (2016) and Wishart et al. (2018)
CYP2C9	Brivaracetam, bupropion, carvedilol, celecoxib, clozapine, dolasetron, dronabinol, eletriptan, felbamate, fluoxetine, nabilone, netupitant, phenobarbital, phenytoin, primidone, quazepam, ramelteon, tapentadol, valproic acid	Bibi 2008), Fernandes et al. (2016), Ghosh et al. (2016), and Wishart et al. (2018)
CYP2C18	Phenobarbital, phenytoin	Wishart et al. (2018)
CYP2C19	Almotriptan, amitriptyline, atomoxetine, benzodiazepine, brivaracetam, diazepam, dronabinol, eletriptan, felbamate, lorcaserin, omeprazole, phenobarbital, phenytoin, primidone, propranolol, quazepam, ramelteon, tapentadol, valproic acid, zonisamide	Bibi 2008), Fernandes et al. (2016), Ghosh et al. (2016), and Wishart et al. (2018)
CYP2D6	Almotriptan, amitriptyline, aripiprazole, aripiprazole lauroxil, atomoxetine, brexpiprazole, brofaromine, bupropion, cariprazine, carvedilol, celecoxib, chlorpromazine, clomipramine, codeine, citalopram, clozapine, desipramine, dextromethorphan, dolasetron, doxepin, duloxetine, eletriptan, ethylmorphine, escitalopram, fluoxetine, fluvoxamine, galantamine, haloperidol, hydrocodone, iloperidone, imipramine, lisdexamfetamine, lorcaserin, mianserin, midomafetamine, mirtazapine, morphine, netupitant, nicergoline, nicotine, nortriptyline, olanzapine, opiate, oxycodone, paliperidone, palonosetron, parathion, paroxetine, perphenazine, phenytoin, pimavanserin, quetiapine, remoxipride, risperidone, sertraline, tapentadol, thioridazine, tramadol, tranylcypromine, trazodone, valbenazine, venlafaxine, vilazodone, vortioxetine, ziprasidone, zuclopenthixol, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)	Smith (2009), Miksys S and Tyndale (2013), Fernandes et al. (2016), Ghosh et al. (2016), Deardorff et al. (2018), and Wishart et al. (2018)
CYP2E1	Acetaminophen, acetone, almotriptan, aniline, aspartame, benzene, bupropion, carbon, carvedilol, chloroform, chlorzoxazone, diethyl ether, enflurane, ethanol, enflurane, felbamate, halothane, isoflurane, methoxyflurane, nabilone, nicotine, phenytoin, phenobarbital, primidone, sevoflurane, tetrachloride, trichloroethylene, trimethadione	Bibi (2008), Miksys S and Tyndale (2013), Fernandes et al. (2016), Ghosh et al. (2016), and Wishart et al. (2018)
CYP2J2	Dronabinol, nabilone, pimavanserin	Fernandes et al. (2016)
CYP3A4	Almotriptan, alprazolam, aripiprazole, aripiprazole lauroxil, brexpiprazole, brivaracetam, bromocriptine, buspirone, carbamazepine, cabergoline, cariprazine, carvedilol, celecoxib, clonazepam, clozapine, desvenlafaxine, dolasetron, donepezil, dronabinol, eletriptan, estazolam, eszopiclone, felbamate, flunitrazepam, fluoxetine, galantamine, haloperidol, levomethadyl, lorcaserin, midazolam, milnacipran, mirtazapine, modafinil, nabilone, naloxegol, nefazodone, netupitant, paliperidone, palonosetron, perampanel, pimavanserin, pimozide, phenytoin, quazepam, ramelteon, reboxetine, risperidone, safinamide, sibutramine, suvorexant, tasimelteon, tiagabine, triazolam, valbenazine, valproate, venlafaxine, zaleplon, ziprasidone, zolpidem, zonisamide, zopiclone	Smith 2009), Fernandes et al. (2016), and Wishart et al. (2018)
CYP3A5	Aripiprazole lauroxil, carbamazepine, fluoxetine, modafinil, paliperidone, perampanel, phenytoin, pimavanserin, valbenazine, valproic acid, zaleplon, zonisamide	Fernandes et al. (2016) and Wishart et al. (2018)
CYP3A7	Aripiprazole lauroxil, levomethadyl, phenytoin, zaleplon	Fernandes et al. (2016) and Wishart et al. (2018)
CYP3A43	Alprazolam, netupitant	Agarwal et al. (2008) and Fernandes et al. (2016)

Table

UGT enzymes	CNS-acting drugs	Ref.
UGT1A1	Acetaminophen, buprenorphine, carvedilol, dronabinol, edaravone, ezogabine, morphine, nalorphine, naltrexone, phenytoin, retigabine, tiagabine, valproic acid, zonisamide	Kiang et al. (2005), Fernandes et al. (2016), and Wishart et al. (2018)
UGT1A3	Amitriptyline, buprenorphine, clozapine, dronabinol, ezogabine, imipramine, morphine, norbuprenorphine, valproic acid	Kiang et al. (2005), Fernandes et al. (2016), and Wishart et al. (2018)
UGT1A4	Amitriptyline, chlorpromazine, clozapine, cotinine, doxepin, ezogabine, imipramine, lamotrigine, 1-OH midazolam, nicotine, olanzapine, phenytoin, retigabine, trifluoperazine, valproic acid	Kiang et al. (2005), Rowland et al. (2013), Fernandes et al. (2016), and Wishart et al. (2018)
UGT1A6	Acetaminophen, edaravone, morphine, phenytoin, valproic acid	Kiang et al. (2005), Rowland et al. (2013), and Wishart et al. (2018)
UGT1A7	Edaravone	Wishart et al. (2018)
UGT1A10	Dronabinol, edaravone, morphine, valproic acid	Kiang et al. (2005), Fernandes et al. (2016), and Wishart et al. (2018)
UGT2B7	Buprenorphine, codeine, carbamazepine, carvedilol, edaravone, haloperidol, lorazepam, morphine, naloxone, naltrexone, nalorphine, (R)-oxazepam, (S)-oxazepam, tapentadol, valproic acid	Kiang et al. (2005), Rowland et al. (2013), Fernandes et al. (2016), Wishart et al. (2018), and Meech et al. (2019)
UGT2B17	Edaravone, eslicarbazepine	Meech et al. (2019)

CNS-active drugs approved by FDA from 1985 to 2014 (Fernandes et al. 2016) and 2015–2023 (https://www.fda.gov/) were allocated to the major CYP and UGT DMEs in human brains according to the metabolic enzymes collected in DrugBank database (Wishart et al. 2018).

Zhang ZQ, Sheng L, Li Y. 2016. Drug glucuronidation and disposition in brain. Yao Xue Xue Bao. 51(11):1674–1680.

 PubMedGoogle Scholar

Walther B, Ghersi-Egea JF, Minn A, Siest G. 1986. Subcellular distribution of cytochrome P-450 in the brain. Brain Res. 375(2):338–344. doi: 10.1016/0006-8993(86)90754-7.

 PubMed Web of Science ®Google Scholar

Šrejber M, Navrátilová V, Paloncýová M, Bazgier V, Berka K, Anzenbacher P, Otyepka M. 2018. Membrane-attached mammalian cytochromes P450: an overview of the membrane’s effects on structure, drug binding, and interactions with redox partners. J Inorg Biochem. 183:117–136. doi: 10.1016/j.jinorgbio.2018.03.002.

 PubMed Web of Science ®Google Scholar

Ouzzine M, Gulberti S, Ramalanjaona N, Magdalou J, Fournel-Gigleux S. 2014. The UDP-glucuronosyltransferases of the blood–brain barrier: their role in drug metabolism and detoxication. Front Cell Neurosci. 8:349. doi: 10.3389/fncel.2014.00349.

 PubMed Web of Science ®Google Scholar

Dutheil F, Beaune P, Loriot MA. 2008. Xenobiotic metabolizing enzymes in the central nervous system: contribution of cytochrome P450 enzymes in normal and pathological human brain. Biochimie. 90(3):426–436. doi: 10.1016/j.biochi.2007.10.007.

 PubMed Web of Science ®Google Scholar

Dutheil F, Dauchy S, Diry M, Sazdovitch V, Cloarec O, Mellottée L, Bièche I, Ingelman-Sundberg M, Flinois J-P, de Waziers I, et al. 2009. Xenobiotic-metabolizing enzymes and transporters in the normal human brain: regional and cellular mapping as a basis for putative roles in cerebral function. Drug Metab Dispos. 37(7):1528–1538. doi: 10.1124/dmd.109.027011.

 PubMed Web of Science ®Google Scholar

Ghosh C, Hossain M, Solanki J, Dadas A, Marchi N, Janigro D. 2016. Pathophysiological implications of neurovascular P450 in brain disorders. Drug Discov Today. 21(10):1609–1619. doi: 10.1016/j.drudis.2016.06.004.

 PubMed Web of Science ®Google Scholar

Sjöstedt E, Zhong W, Fagerberg L, Karlsson M, Mitsios N, Adori C, Oksvold P, Edfors F, Limiszewska A, Hikmet F, et al. 2020. An atlas of the protein-coding genes in the human, pig, and mouse brain. Science. 367(6482). doi: 10.1126/science.aay5947.

 Google Scholar

Bhagwat SV, Boyd MR, Ravindranath V. 2000. Multiple forms of cytochrome P450 and associated monooxygenase activities in human brain mitochondria. Biochem Pharmacol. 59(5):573–582. doi: 10.1016/s0006-2952(99)00362-7.

 PubMed Web of Science ®Google Scholar

Miksys SL, Tyndale RF. 2002. Drug-metabolizing cytochrome P450s in the brain. J Psychiatry Neurosci. 27(6):406–415.

 PubMed Web of Science ®Google Scholar

Schilter B, Omiecinski CJ. 1993. Regional distribution and expression modulation of cytochrome P-450 and epoxide hydrolase mRNAs in the rat brain. Mol Pharmacol. 44(5):990–996.

 PubMed Web of Science ®Google Scholar

Morse DC, Stein AP, Thomas PE, Lowndes HE. 1998. Distribution and induction of cytochrome P450 1A1 and 1A2 in rat brain. Toxicol Appl Pharmacol. 152(1):232–239. doi: 10.1006/taap.1998.8477.

 PubMed Web of Science ®Google Scholar

Iba MM, Storch A, Ghosal A, Bennett S, Reuhl KR, Lowndes HE. 2003. Constitutive and inducible levels of CYP1A1 and CYP1A2 in rat cerebral cortex and cerebellum. Arch Toxicol. 77(10):547–554. doi: 10.1007/s00204-003-0488-1.

 PubMed Web of Science ®Google Scholar

Dey A, Jones JE, Nebert DW. 1999. Tissue- and cell type-specific expression of cytochrome P450 1A1 and cytochrome P450 1A2 mRNA in the mouse localized in situ hybridization. Biochem Pharmacol. 58(3):525–537. doi: 10.1016/s0006-2952(99)00110-0.

 PubMed Web of Science ®Google Scholar

Huang P, Rannug A, Ahlbom E, Håkansson H, Ceccatelli S. 2000. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the expression of cytochrome P450 1A1, the aryl hydrocarbon receptor, and the aryl hydrocarbon receptor nuclear translocator in rat brain and pituitary. Toxicol Appl Pharmacol. 169(2):159–167. doi: 10.1006/taap.2000.9064.

 PubMed Web of Science ®Google Scholar

Meyer RP, Podvinec M, Meyer UA. 2002. Cytochrome P450 CYP1A1 accumulates in the cytosol of kidney and brain and is activated by heme. Mol Pharmacol. 62(5):1061–1067. doi: 10.1124/mol.62.5.1061.

 PubMed Web of Science ®Google Scholar

Granberg L, Ostergren A, Brandt I, Brittebo EB. 2003. CYP1A1 and CYP1B1 in blood–brain interfaces: CYP1A1-dependent bioactivation of 7,12-dimethylbenz(a)anthracene in endothelial cells. Drug Metab Dispos. 31(3):259–265. doi: 10.1124/dmd.31.3.259.

 PubMed Web of Science ®Google Scholar

Farin FM, Omiecinski CJ. 1993. Regiospecific expression of ­cytochrome P-450s and microsomal epoxide hydrolase in human brain tissue. J Toxicol Environ Health. 40(2–3):317–335. doi: 10.1080/15287399309531797.

 PubMed Web of Science ®Google Scholar

McFadyen MCE, Melvin WT, Murray GI. 1998. Regional distribution of individual forms of cytochrome P450 mRNA in normal adult human brain. Biochem Pharmacol. 55(6):825–830. doi: 10.1016/s0006-2952(97)00516-9.

 PubMed Web of Science ®Google Scholar

Fanni D, Pinna F, Gerosa C, Paribello P, Carpiniello B, Faa G, Manchia M. 2021. Anatomical distribution and expression of CYP in humans: neuropharmacological implications. Drug Dev Res. 82(5):628–667. doi: 10.1002/ddr.21778.

 PubMed Web of Science ®Google Scholar

Stamou M, Wu X, Kania-Korwel I, Lehmler HJ, Lein PJ. 2014. Cytochrome p450 mRNA expression in the rodent brain: species-, sex-, and region-dependent differences. Drug Metab Dispos. 42(2):239–244. doi: 10.1124/dmd.113.054239.

 PubMed Web of Science ®Google Scholar

Rieder CR, Ramsden DB, Williams AC. 1998. Cytochrome P450 1B1 mRNA in the human central nervous system. Mol Pathol. 51(3):138–142. doi: 10.1136/mp.51.3.138.

 PubMedGoogle Scholar

Murray GI, Taylor MC, McFadyen MC, McKay JA, Greenlee WF, Burke MD, Melvin WT. 1997. Tumor-specific expression of cytochrome P450 CYP1B1. Cancer Res. 57(14):3026–3031.

 PubMed Web of Science ®Google Scholar

Rieder CRM, Parsons RB, Fitch NJS, Williams AC, Ramsden DB. 2000. Human brain cytochrome P450 1B1: immunohistochemical localization in human temporal lobe and induction by dimethylbenz(a)anthracene in astrocytoma cell line (MOG-G-CCM). Neurosci Lett. 278(3):177–180. doi: 10.1016/s0304-3940(99)00932-5.

 PubMed Web of Science ®Google Scholar

Muskhelishvili L, Thompson PA, Kusewitt DF, Wang C, Kadlubar FF. 2001. In situ hybridization and immunohistochemical analysis of cytochrome P450 1B1 expression in human normal tissues. J Histochem Cytochem. 49(2):229–236. doi: 10.1177/002215540104900210.

 PubMed Web of Science ®Google Scholar

Dauchy S, Dutheil F, Weaver RJ, Chassoux F, Daumas-Duport C, Couraud PO, Scherrmann JM, De Waziers I, Decleves X. 2008. ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood–brain barrier. J Neurochem. 107(6):1518–1528. doi: 10.1111/j.1471-4159.2008.05720.x.

 PubMed Web of Science ®Google Scholar

Yu X, Wu J, Hu M, Wu J, Zhu Q, Yang Z, Xie X, Feng YQ, Yue J. 2019. Glutamate affects the CYP1B1- and CYP2U1-mediated hydroxylation of arachidonic acid metabolism via astrocytic mGlu5 receptor. Int J Biochem Cell Biol. 110:111–121. doi: 10.1016/j.biocel.2019.03.001.

 PubMed Web of Science ®Google Scholar

Oguro A, Ishihara Y, Siswanto FM, Yamazaki T, Ishida A, Imaishi H, Imaoka S. 2021. Contribution of DHA diols (19,20-DHDP) produced by cytochrome P450s and soluble epoxide hydrolase to the beneficial effects of DHA supplementation in the brains of rotenone-induced rat models of Parkinson’s disease. Biochim Biophys Acta Mol Cell Biol Lipids. 1866(2):158858. doi: 10.1016/j.bbalip.2020.158858.

 PubMed Web of Science ®Google Scholar

Volk B, Meyer RP, von Lintig F, Ibach B, Knoth R. 1995. Localization and characterization of cytochrome P450 in the brain. In vivo and in vitro investigations on phenytoin- and phenobarbital-inducible isoforms. Toxicol Lett. 82–83:655–662. doi: 10.1016/0378-4274(95)03511-7.

 PubMed Web of Science ®Google Scholar

Miksys S, Hoffmann E, Tyndale RF. 2000. Regional and cellular induction of nicotine-metabolizing CYP2B1 in rat brain by chronic nicotine treatment. Biochem Pharmacol. 59(12):1501–1511. doi: 10.1016/s0006-2952(00)00281-1.

 PubMed Web of Science ®Google Scholar

Miksys S, Lerman C, Shields PG, Mash DC, Tyndale RF. 2003. Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain. Neuropharmacology. 45(1):122–132. doi: 10.1016/s0028-3908(03)00136-9.

 PubMed Web of Science ®Google Scholar

Thuerl C, Otten U, Knoth R, Meyer RP, Volk B. 1997. Possible role of cytochrome P450 in inactivation of testosterone in immortalized hippocampal neurons. Brain Res. 762(1–2):47–55. doi: 10.1016/s0006-8993(97)00259-x.

 PubMed Web of Science ®Google Scholar

Riedl AG, Watts PM, Douek DC, Edwards RJ, Boobis AR, Rose S, Jenner P. 2000. Expression and distribution of CYP2C enzymes in rat basal ganglia. Synapse. 38(4):392–402. doi: 10.1002/1098-2396(20001215)38:4<392::AID-SYN4>3.0.CO;2-Z.

 PubMed Web of Science ®Google Scholar

Booth Depaz IM, Toselli F, Wilce PA, Gillam EM. 2015. Differential expression of cytochrome P450 enzymes from the CYP2C subfamily in the human brain. Drug Metab Dispos. 43(3):353–357. doi: 10.1124/dmd.114.061242.

 PubMed Web of Science ®Google Scholar

Alkayed NJ, Narayanan J, Gebremedhin D, Medhora M, Roman RJ, Harder DR. 1996. Molecular characterization of an arachidonic acid epoxygenase in rat brain astrocytes. Stroke. 27(5):971–979. doi: 10.1161/01.str.27.5.971.

 PubMed Web of Science ®Google Scholar

Navarro-Mabarak C, Loaiza-Zuluaga M, Hernández-Ojeda SL, Camacho-Carranza R, Espinosa-Aguirre JJ. 2020. Neuroinflammation is able to downregulate cytochrome P450 epoxygenases 2J3 and 2C11 in the rat brain. Brain Res Bull. 163:57–64. doi: 10.1016/j.brainresbull.2020.07.016.

 PubMed Web of Science ®Google Scholar

Meyer RP, Knoth R, Schiltz E, Volk B. 2001. Possible function of astrocyte cytochrome P450 in control of xenobiotic phenytoin in the brain: in vitro studies on murine astrocyte primary cultures. Exp Neurol. 167(2):376–384. doi: 10.1006/exnr.2000.7553.

 PubMed Web of Science ®Google Scholar

Miksys S, Rao Y, Sellers EM, Kwan M, Mendis D, Tyndale RF. 2000. Regional and cellular distribution of CYP2D subfamily members in rat brain. Xenobiotica. 30(6):547–564. doi: 10.1080/004982500406390.

 PubMed Web of Science ®Google Scholar

Gilbert EA, Edwards RJ, Boobis AR, Rose S, Jenner P. 2003. Differential expression of cytochrome P450 enzymes in cultured and intact foetal rat ventral mesencephalon. J Neural Transm. 110(10):1091–1101. doi: 10.1007/s00702-003-0029-3.

 PubMed Web of Science ®Google Scholar

Funae Y, Kishimoto W, Cho T, Niwa T, Hiroi T. 2003. CYP2D in the brain. Drug Metab Pharmacokinet. 18(6):337–349. doi: 10.2133/dmpk.18.337.

 PubMedGoogle Scholar

Riedl AG, Watts PM, Edwards RJ, Schulz-Utermoehl T, Boobis AR, Jenner P, Marsden CD. 1999. Expression and localisation of CYP2D enzymes in rat basal ganglia. Brain Res. 822(1–2):175–191. doi: 10.1016/s0006-8993(99)01113-0.

 PubMed Web of Science ®Google Scholar

Siegle I, Fritz P, Eckhardt K, Zanger UM, Eichelbaum M. 2001. Cellular localization and regional distribution of CYP2D6 mRNA and protein expression in human brain. Pharmacogenetics. 11(3):237–245. doi: 10.1097/00008571-200104000-00007.

 PubMedGoogle Scholar

Chinta SJ, Pai HV, Upadhya SC, Boyd MR, Ravindranath V. 2002. Constitutive expression and localization of the major drug metabolizing enzyme, cytochrome P4502D in human brain. Brain Res Mol Brain Res. 103 (1–2):49–61. doi: 10.1016/s0169-328x(02)00177-8.

 PubMedGoogle Scholar

Singh S, Singh K, Patel DK, Singh C, Nath C, Singh VK, Singh RK, Singh MP. 2009. The expression of CYP2D22, an ortholog of human CYP2D6, in mouse striatum and its modulation in 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease phenotype and nicotine-mediated neuroprotection. Rejuvenat Res. 12(3):185–197. doi: 10.1089/rej.2009.0850.

 PubMed Web of Science ®Google Scholar

Toselli F, Booth Depaz IM, Worrall S, Etheridge N, Dodd PR, Wilce PA, Gillam EM. 2015. Expression of CYP2E1 and CYP2U1 proteins in amygdala and prefrontal cortex: influence of alcoholism and smoking. Alcohol Clin Exp Res. 39(5):790–797. doi: 10.1111/acer.12697.

 PubMed Web of Science ®Google Scholar

Boussadia B, Ghosh C, Plaud C, Pascussi JM, de Bock F, Rousset MC, Janigro D, Marchi N. 2014. Effect of status epilepticus and antiepileptic drugs on CYP2E1 brain expression. Neuroscience. 281:124–134. doi: 10.1016/j.neuroscience.2014.09.055.

 PubMed Web of Science ®Google Scholar

Liu M, Zhu Q, Wu J, Yu X, Hu M, Xie X, Yang Z, Yang J, Feng YQ, Yue J. 2017. Glutamate affects the production of epoxyeicosanoids within the brain: the up-regulation of brain CYP2J through the MAPK–CREB signaling pathway. Toxicology. 381:31–38. doi: 10.1016/j.tox.2017.02.008.

 PubMed Web of Science ®Google Scholar

Woodland C, Huang TT, Gryz E, Bendayan R, Fawcett JP. 2008. Expression, activity and regulation of CYP3A in human and rodent brain. Drug Metab Rev. 40(1):149–168. doi: 10.1080/03602530701836712.

 PubMed Web of Science ®Google Scholar

Vences-Mejía A, Labra-Ruíz N, Hernández-Martínez N, Dorado-González V, Gómez-Garduño J, Pérez-López I, Nosti-Palacios R, Camacho Carranza R, Espinosa-Aguirre JJ. 2006. The effect of aspartame on rat brain xenobiotic-metabolizing enzymes. Hum Exp Toxicol. 25(8):453–459. doi: 10.1191/0960327106het646oa.

 PubMed Web of Science ®Google Scholar

Vences-Mejía A, Gómez-Garduño J, Caballero-Ortega H, Dorado-González V, Nosti-Palacios R, Labra-Ruíz N, Espinosa-Aguirre JJ. 2012. Effect of mosquito mats (pyrethroid-based) vapor inhalation on rat brain cytochrome P450s. Toxicol Mech Methods. 22(1):41–46. doi: 10.3109/15376516.2011.591448.

 PubMed Web of Science ®Google Scholar

Voirol P, Jonzier-Perey M, Porchet F, Reymond MJ, Janzer RC, Bouras C, Strobel HW, Kosel M, Eap CB, Baumann P. 2000. Cytochrome P-450 activities in human and rat brain microsomes. Brain Res. 855(2):235–243. doi: 10.1016/s0006-8993(99)02354-9.

 PubMed Web of Science ®Google Scholar

Murray GI, Pritchard S, Melvin WT, Burke MD. 1995. Cytochrome P450 CYP3A5 in the human anterior pituitary gland. FEBS Lett. 364(1):79–82. doi: 10.1016/0014-5793(95)00367-i.

 PubMed Web of Science ®Google Scholar

Wang H, Kawashima H, Strobel HW. 1996. cDNA cloning of a novel CYP3A from rat brain. Biochem Biophys Res Commun. 221(1):157–162. doi: 10.1006/bbrc.1996.0562.

 PubMed Web of Science ®Google Scholar

Hagemeyer CE, Rosenbrock H, Ditter M, Knoth R, Volk B. 2003. Predominantly neuronal expression of cytochrome P450 isoforms CYP3A11 and CYP3A13 in mouse brain. Neuroscience. 117(3):521–529. doi: 10.1016/s0306-4522(02)00955-7.

 PubMed Web of Science ®Google Scholar

Kutsuno Y, Hirashima R, Sakamoto M, Ushikubo H, Michimae H, Itoh T, Tukey RH, Fujiwara R. 2015. Expression of UDP-glucuronosyltransferase 1 (UGT1) and glucuronidation activity toward endogenous substances in humanized UGT1 mouse brain. Drug Metab Dispos. 43(7):1071–1076. doi: 10.1124/dmd.115.063719.

 PubMed Web of Science ®Google Scholar

Shelby MK, Cherrington NJ, Vansell NR, Klaassen CD. 2003. Tissue mRNA expression of the rat UDP-glucuronosyltransferase gene family. Drug Metab Dispos. 31(3):326–333. doi: 10.1124/dmd.31.3.326.

 PubMed Web of Science ®Google Scholar

Gambaro SE, Robert MC, Tiribelli C, Gazzin S. 2016. Role of brain cytochrome P450 mono-oxygenases in bilirubin oxidation-specific induction and activity. Arch Toxicol. 90(2):279–290. doi: 10.1007/s00204-014-1394-4.

 PubMed Web of Science ®Google Scholar

Togna AR, Antonilli L, Dovizio M, Salemme A, De Carolis L, Togna GI, Patrignani P, Nencini P. 2013. In vitro morphine metabolism by rat microglia. Neuropharmacology. 75:391–398. doi: 10.1016/j.neuropharm.2013.08.019.

 PubMed Web of Science ®Google Scholar

Heydel JM, Holsztynska EJ, Legendre A, Thiebaud N, Artur Y, Le Bon AM. 2010. UDP-glucuronosyltransferases (UGTs) in neuro-olfactory tissues: expression, regulation, and function. Drug Metab Rev. 42(1):74–97. doi: 10.3109/03602530903208363.

 PubMed Web of Science ®Google Scholar

Court MH, Zhang X, Ding X, Yee KK, Hesse LM, Finel M. 2012. Quantitative distribution of mRNAs encoding the 19 human UDP-glucuronosyltransferase enzymes in 26 adult and 3 fetal tissues. Xenobiotica. 42(3):266–277. doi: 10.3109/00498254.2011.618954.

 PubMed Web of Science ®Google Scholar

King CD, Rios GR, Assouline JA, Tephly TR. 1999. Expression of UDP-glucuronosyltransferases (UGTs) 2B7 and 1A6 in the human brain and identification of 5-hydroxytryptamine as a substrate. Arch Biochem Biophys. 365(1):156–162. English. doi: 10.1006/abbi.1999.1155.

 PubMed Web of Science ®Google Scholar

Gradinaru D, Minn AL, Artur Y, Minn A, Heydel JM. 2009. Drug metabolizing enzyme expression in rat choroid plexus: effects of in vivo xenobiotics treatment. Arch Toxicol. 83(6):581–586. doi: 10.1007/s00204-008-0386-7.

 PubMed Web of Science ®Google Scholar

Sakakibara Y, Katoh M, Kondo Y, Nadai M. 2016. Effects of beta-naphthoflavone on Ugt1a6 and Ugt1a7 expression in rat brain. Biol Pharm Bull. 39(1):78–83. doi: 10.1248/bpb.b15-00578.

 PubMed Web of Science ®Google Scholar

Suleman FG, Ghersi-Egea JF, Leininger-Muller B, Minn A. 1993. Uridine diphosphate-glucuronosyltransferase activities in rat brain microsomes. Neurosci Lett. 161(2):219–222. doi: 10.1016/0304-3940(93)90298-y.

 PubMed Web of Science ®Google Scholar

Martignoni M, Groothuis GM, de Kanter R. 2006. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol. 2(6):875–894. doi: 10.1517/17425255.2.6.875.

 PubMed Web of Science ®Google Scholar

Nagai K, Fukuno S, Suzuki H, Konishi H. 2016. Higher gene expression of CYP1A2, 2B1 and 2D2 in the brain of female compared with male rats. Pharmazie. 71(6):334–336.

 PubMed Web of Science ®Google Scholar

Sayers EW, Beck J, Bolton EE, Bourexis D, Brister JR, Canese K, Comeau DC, Funk K, Kim S, Klimke W, et al. 2021. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 49(D1):D10–D17. doi: 10.1093/nar/gkaa892.

 PubMed Web of Science ®Google Scholar

Jacob A, Hartz AM, Potin S, Coumoul X, Yousif S, Scherrmann J-M, Bauer B, Declèves X. 2011. Aryl hydrocarbon receptor-dependent upregulation of Cyp1b1 by TCDD and diesel exhaust particles in rat brain microvessels. Fluids Barriers CNS. 8(1):23. doi: 10.1186/2045-8118-8-23.

 PubMedGoogle Scholar

Imaoka S, Hashizume T, Funae Y. 2005. Localization of rat ­cytochrome P450 in various tissues and comparison of ­arachidonic acid metabolism by rat P450 with that by ­human P450 orthologs. Drug Metab Pharmacokinet. 20(6):478–484. doi: 10.2133/dmpk.20.478.

 PubMedGoogle Scholar

Yu Y, Fuscoe JC, Zhao C, Guo C, Jia M, Qing T, Bannon DI, Lancashire L, Bao W, Du T, et al. 2014. A rat RNA-Seq transcriptomic BodyMap across 11 organs and 4 developmental stages. Nat Commun. 5(1):3230. doi: 10.1038/ncomms4230.

 PubMed Web of Science ®Google Scholar

Yue F, Cheng Y, Breschi A, Vierstra J, Wu W, Ryba T, Sandstrom R, Ma Z, Davis C, Pope BD, et al. 2014. A comparative encyclopedia of DNA elements in the mouse genome. Nature. 515(7527):355–364. doi: 10.1038/nature13992.

 PubMed Web of Science ®Google Scholar

Kiang TK, Ensom MH, Chang TK. 2005. UDP-glucuronosyltransferases and clinical drug–drug interactions. Pharmacol Ther. 106(1):97–132. doi: 10.1016/j.pharmthera.2004.10.013.

 PubMed Web of Science ®Google Scholar

Nakajima M, Yamanaka H, Fujiwara R, Katoh M, Yokoi T. 2007. Stereoselective glucuronidation of 5-(4′-hydroxyphenyl)-5-phenylhydantoin by human UDP-glucuronosyltransferase (UGT) 1A1, UGT1A9, and UGT2B15: effects of UGT-UGT interactions. Drug Metab Dispos. 35(9):1679–1686. doi: 10.1124/dmd.107.015909.

 PubMed Web of Science ®Google Scholar

Jancova P, Anzenbacher P, Anzenbacherova E. 2010. Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 154(2):103–116. doi: 10.5507/bp.2010.017.

 PubMed Web of Science ®Google Scholar

Rowland A, Miners JO, Mackenzie PI. 2013. The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification. Int J Biochem Cell Biol. 45(6):1121–1132. doi: 10.1016/j.biocel.2013.02.019.

 PubMed Web of Science ®Google Scholar

Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, et al. 2018. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 46(D1):D1074–D1082. doi: 10.1093/nar/gkx1037.

 PubMed Web of Science ®Google Scholar

Meech R, Hu DG, McKinnon RA, Mubarokah SN, Haines AZ, Nair PC, Rowland A, Mackenzie PI. 2019. The UDP-glycosyltransferase (UGT) superfamily: new members, new functions, and novel paradigms. Physiol Rev. 99(2):1153–1222. doi: 10.1152/physrev.00058.2017.

 PubMed Web of Science ®Google Scholar

Frommer WB, Davidson MW, Campbell RE. 2009. Genetically encoded biosensors based on engineered fluorescent proteins. Chem Soc Rev. 38(10):2833–2841. doi: 10.1039/b907749a.

 PubMed Web of Science ®Google Scholar

Johansson MK, Cook RM. 2003. Intramolecular dimers: a new design strategy for fluorescence-quenched probes. Chemistry. 9(15):3466–3471. doi: 10.1002/chem.200304941.

 PubMed Web of Science ®Google Scholar

Galis ZS, Sukhova GK, Lark MW, Libby P. 1994. Increased ­expression of matrix metalloproteinases and matrix ­degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 94(6):2493–2503. doi: 10.1172/JCI117619.

 PubMed Web of Science ®Google Scholar

Weissleder R, Tung CH, Mahmood U, Bogdanov AJr. 1999. In vivo imaging of tumors with protease-activated near-infrared fluorescent probes. Nat Biotechnol. 17(4):375–378. doi: 10.1038/7933.

 PubMed Web of Science ®Google Scholar

Kwan DH, Chen HM, Ratananikom K, Hancock SM, Watanabe Y, Kongsaeree PT, Samuels AL, Withers SG. 2011. Self-immobilizing fluorogenic imaging agents of enzyme activity. Angew Chem Int Ed Engl. 50(1):300–303. doi: 10.1002/anie.201005705.

 PubMed Web of Science ®Google Scholar

Vandooren J, Geurts N, Martens E, Van den Steen PE, Opdenakker G. 2013. Zymography methods for visualizing hydrolytic enzymes. Nat Methods. 10(3):211–220. doi: 10.1038/nmeth.2371.

 PubMed Web of Science ®Google Scholar

Kanamori K, Ross BD. 2005. Suppression of glial glutamine release to the extracellular fluid studied in vivo by NMR and microdialysis in hyperammonemic rat brain. J Neurochem. 94(1):74–85. doi: 10.1111/j.1471-4159.2005.03170.x.

 PubMed Web of Science ®Google Scholar

Dona AC, Kyriakides M, Scott F, Shephard EA, Varshavi D, Veselkov K, Everett JR. 2016. A guide to the identification of metabolites in NMR-based metabonomics/metabolomics experiments. Comput Struct Biotechnol J. 14:135–153. doi: 10.1016/j.csbj.2016.02.005.

 PubMed Web of Science ®Google Scholar

Kanamori K. 2017. In vivo N-15 MRS study of glutamate metabolism in the rat brain. Anal Biochem. 529:179–192. doi: 10.1016/j.ab.2016.08.025.

 PubMed Web of Science ®Google Scholar

Rackayova V, Cudalbu C, Pouwels PJW, Braissant O. 2017. Creatine in the central nervous system: from magnetic resonance spectroscopy to creatine deficiencies. Anal Biochem. 529:144–157. doi: 10.1016/j.ab.2016.11.007.

 PubMed Web of Science ®Google Scholar

Greis KD. 2007. Mass spectrometry for enzyme assays and inhibitor screening: an emerging application in pharmaceutical research. Mass Spectrom Rev. 26(3):324–339. doi: 10.1002/mas.20127.

 PubMed Web of Science ®Google Scholar

Koehbach J, Gruber CW, Becker C, Kreil DP, Jilek A. 2016. MALDI TOF/TOF-based approach for the identification of d-amino acids in biologically active peptides and proteins. J Proteome Res. 15(5):1487–1496. doi: 10.1021/acs.jproteome.5b01067.

 PubMed Web of Science ®Google Scholar

OuYang C, Chen B, Li L. 2015. High throughput in situ DDA analysis of neuropeptides by coupling novel multiplex mass spectrometric imaging (MSI) with gas-phase fractionation. J Am Soc Mass Spectrom. 26(12):1992–2001. doi: 10.1007/s13361-015-1265-0.

 PubMed Web of Science ®Google Scholar

Wang Y, Zagorevski DV, Lennartz MR, Loegering DJ, Stenken JA. 2009. Detection of in vivo matrix metalloproteinase activity using microdialysis sampling and liquid chromatography/mass spectrometry. Anal Chem. 81(24):9961–9971. doi: 10.1021/ac901703g.

 PubMed Web of Science ®Google Scholar

Wu J, Xu K, Landers JP, Weber SG. 2013. An in situ measurement of extracellular cysteamine, homocysteine, and cysteine concentrations in organotypic hippocampal slice cultures by integration of electroosmotic sampling and microfluidic analysis. Anal Chem. 85(6):3095–3103. doi: 10.1021/ac302676q.

 PubMed Web of Science ®Google Scholar

Rupert AE, Ou Y, Sandberg M, Weber SG. 2013. Electroosmotic push–pull perfusion: description and application to qualitative analysis of the hydrolysis of exogenous galanin in organotypic hippocampal slice cultures. ACS Chem Neurosci. 4(5):838–848. doi: 10.1021/cn400082d.

 PubMed Web of Science ®Google Scholar

Fernandes TB, Damião MCF, Polli M, Parise-Filho R. 2016. Analysis of the applicability and use of Lipinski’s rule for central nervous system drugs. Lett Drug Des Discov. 13(10):999–1006. doi: 10.2174/1570180813666160622092839.

 Web of Science ®Google Scholar

Miksys S, Tyndale RF. 2013. Cytochrome P450-mediated drug metabolism in the brain. J Psychiatry Neurosci. 38(3):152–163. doi: 10.1503/jpn.120133.

 PubMed Web of Science ®Google Scholar

Bibi Z. 2008. Role of cytochrome P450 in drug interactions. Nutr Metab. 5(1):27. doi: 10.1186/1743-7075-5-27.

 Google Scholar

Smith HS. 2009. Opioid metabolism. Mayo Clin Proc. 84(7):613–624. doi: 10.1016/S0025-6196(11)60750-7.

 PubMed Web of Science ®Google Scholar

Deardorff OG, Jenne V, Leonard L, Ellingrod VL. 2018. Making sense of CYP2D6 and CYP1A2 genotype vs phenotype. Curr Psychiatry. 17:41–45.

 Google Scholar

Agarwal V, Kommaddi RP, Valli K, Ryder D, Hyde TM, Kleinman JE, Strobel HW, Ravindranath V. 2008. Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite. PLOS One. 3(6):e2337. doi: 10.1371/journal.pone.0002337.

 PubMed Web of Science ®Google Scholar