Sucralose, A Synthetic Organochlorine Sweetener: Overview Of Biological Issues

Figures & data

TABLE 1.  Significant Changes in the Expression of P-gp, CYP3A, and CYP2D Subsequent to Sucralose Ingestion (Delivered in Splenda) Relative to Control (No Sucralose) in Rat

	Sucralose dosage (mg/kg/d)	P-gp	CYP3A	CYP2D
Treatment	1.1	—	—	—
	3.3	↑143.5%	↑43.5%	↑36.7%
	5.5	↑122.6%	↑70.0%	↑152.1%
	11	↓64%	↑151.3%	↑249.3%
Recovery	1.1	—	—	—
	3.3	↑16%	—	—
	5.5	↑56.8%	—	↑32.9%
	11	↑82.2%	↑22.4%	↑22.1%
Note. Data from Abou-Donia et al. (2008).

TABLE 2.  Representative Organochlorine Drugs Reported to Be Substrates, Inhibitors, or Inducers of CYP isozymes and/or P-gp Using One or More Assay Types

Drug types	Interactions with CYP and/or P-gp	References
Anticancer drugs
Cyclophosphamide	CYP	Lemke et al., 2008; Pharmacogenomics Knowledge Base, 2009; Baumhäkel et al., 2001; Chang et al., 1997
Ifosfamide	CYP	Lemke et al., 2008; Pharmacogenomics Knowledge Base, 2013; Baumhäkel et al., 2001; Chang et al., 1997
Lomustine	CYP	Le Guellec et al., 1993
Sorafenib	CYP, P-gp	Flaherty et al., 2011; Hu et al., 2009
Toremifene	CYP, P-gp	Berthou et al., 1994; Rao et al., 1994
Trofosfamide	CYP	May-Manke et al., 1999
Cardiovascular and related drugs
Amlodipine	CYP, P-gp	Flockhart, 2013; Katoh et al., 2000a,b
Clofibrate	CYP	Sérée et al., 2004; Adas et al., 1998; Preissner et al., 2010
Clopidogrel	CYP	Guengerich, 1999; Nishiya et al., 2009
Felodipine	CYP, P-gp	Flockhart, 2013; Guengerich, 1999; Wang et al., 2001
Fenofibrate	CYP, P-gp	Flockhart, 2013; Kim and Mancano, 2003; Ehrhardt et al., 2004; Miller and Spence, 1998
Guanabenz	CYP	Clement and Demesmaeke, 1997
Losartan	CYP, P-gp	Flockhart, 2013; Guengerich, 1999; Soldner et al., 2000
Ticlopidine	CYP	Flockhart, 2013; Nishiya et al., 2009; Ieiri et al., 2005
Tienilic acid	CYP	Jean et al., 1996
Anti-inflammatory drugs
Aceclofenac	CYP	Bort et al., 1996
Diclofenac	CYP	Tang et al., 1999; Bort et al., 1999; Flockhart, 2013; Isoherranen et al., 2009
Indomethacin	CYP	Flockhart, 2013; Weaver et al., 1993
Lornoxicam	CYP	Flockhart, 2013; Guo et al., 2005
Anti-infective drugs
Amodiaquine	CYP	Li et al., 2002: Flockhart, 2013; Bapiro et al., 2001
Atovaquone	CYP	van de Poll, 2001
Chloramphenicol	CYP	Flockhart, 2013; Park et al., 2003
Chloroquine	CYP, P-gp	Simooya et al., 1998, Projean et al., 2003, Polli et al., 2001
Clofazimine	CYP, P-gp	Preissner et al., 2010; Wang et al., 2001
Clotrimazole	CYP, P-gp	Isoherranen et al., 2009; Schuetz et al., 1996; Draper et al., 1997; Walsky et al., 2005a; Zhang et al., 2002; Geick et al., 2001; Bain and LeBlanc, 1996; Faucette et al., 2004
Econazole	CYP	Tassaneeyakul et al., 1998
Flucloxacillin	CYP, P-gp	Huwyler et al., 2006
Griseofulvin	CYP	Yasuda et al., 2008
Halofantrine	CYP	Flockhart, 2013; Simooya et al., 1998; Baune et al., 1999
Itraconazole	CYP, P-gp	Isoherranen et al., 2009; Flockhart, 2013; Lemke et al., 2008; Wang et al., 2002; Takara et al., 1999; Miyama et al., 1998
Ketoconazole	CYP, P-gp	Isoherranen et al., 2009, Lemke et al., 2008; Flockhart, 2013; Takano et al., 1998; Wang et al., 2001, 2002; Choo et al., 2000
Miconazole	CYP, P-gp	Isoherranen et al., 2009; Zhang et al., 2002; Ekins et al., 2002; Schwab et al., 2003
Niclosamide	CYP	Bapiro et al., 2001
Oxiconazole	CYP	Svecova et al., 2008
Proguanil	CYP	Flockhart, 2013; Hoskins et al., 1998; Bapiro et al., 2001; Guengerich, 1999
Psychotropic drugs
Adinazolam	CYP	Venkatakrishnan et al., 1998
Alpidem	CYP	Berson et al., 2001; Need et al., 2005; Guengerich, 1999
Alprazolam	CYP	Flockhart, 2013; Yasui et al., 1996; Zhou et al., 2009
(Continued)

TABLE 2.  (Continued)

Drug types	Interactions with CYP and/or P-gp	References
Aripiprazole	CYP	Waade et al., 2009, Flockhart, 2013; Harrison and Perry, 2004
Brotizolam	CYP	Tokairin et al., 2005
Bupropion	CYP	Flockhart, 2013; Faucette et al., 2000; Kotlyar et al., 2005
Chlordiazepoxide	CYP, P-gp	Tomaszewski et al., 2008; Lima et al., 2008
Chlormethiazole	CYP	Isoherranen et al., 2009
Chlorpromazine	CYP, P-gp	Yoshii et al., 2000; Flockhart, 2013; Lemke et al., 2008; Boulton et al., 2002; Ibrahim et al., 2000
Clobazam	CYP	Giraud et al., 2004
Clomipramine	CYP, P-gp	Gardiner and Begg, 2006; Flockhart, 2013; Ibrahim et al., 2000; Gerebtzoff, 2006
Clonazepam	CYP	Lemke et al., 2008
Clotiazepam	CYP	Niwa et al., 2005
Clozapine	CYP, P-gp	Prior et al., 1999; Olesen and Linnet, 2001; Flockhart, 2013; Pirmohamed et al., 1995; Lemke et al., 2008; Ibrahim et al., 2000
Diazepam	CYP, P-gp	Gardiner and Begg, 2006; Flockhart, 2013; Ono et al., 1996; Lima et al., 2008
Estazolam	CYP	Miura et al., 2005
Eszopiclone	CYP	Najib, 2006
Haloperidol	CYP, P-gp	Gardiner and Begg, 2006; Flockhart, 2013; Lemke et al., 2008; Ibrahim et al., 2000; Iwaki et al., 2006; Kudo and Odomi, 1998
Midazolam	CYP, P-gp	Flockhart, 2013; Gorski et al., 1994; Tolle-Sander et al., 2003; Schuetz et al., 1996; Takano et al., 1998
Moclobemide	CYP	Bonnet, 2003; Flockhart, 2013
Nefazodone	CYP, P-gp	Isoherranen et al., 2009; Flockhart, 2013; Störmer et al., 2001
Nordiazepam	CYP	Ono et al., 1996
Perphenazine	CYP	Isoherranen et al., 2009; Flockhart, 2013; Olesen and Linnet, 2000
Sertindole	CYP	Prior et al., 1999; Guengerich, 1999
Sertraline	CYP, P-gp	Flockhart, 2013; Obach et al., 2005; Weiss et al., 2003; Wang et al., 2008
Temazepam	CYP	Ono et al., 1996
Trazodone	CYP, P-gp	Flockhart, 2013; Rotzinger et al., 1998; Mahar Doan et al., 2002; Gerebtzoff, 2006; Störmer et al., 2001; Wen et al., 2008
Triazolam	CYP	Flockhart, 2013; von Moltke et al., 1996; Ong et al., 2000
Ziprasidone	CYP	Flockhart, 2013; Prakash et al., 2000
Zopiclone	CYP	Becquemont et al., 1999
Zotepine	CYP	Shiraga et al., 1999
Zuclopenthixol	CYP	Gardiner and Begg, 2006; Flockhart, 2013
Anesthestics
Enflurane	CYP	Kharasch and Thummel, 1993; Flockhart, 2013
Halothane	CYP	Spracklin et al., 1997; Flockhart, 2013
Isoflurane	CYP	Kharasch and Thummel, 1993; Flockhart, 2013
Ketamine	CYP	Hijazi and Boulieu, 2002
Methoxyflurane	CYP	Kharasch and Thummel, 1993; Flockhart, 2013
Antihistamines
Azelastine	CYP, P-gp	Nakajima et al., 1999a,b; Katoh et al., 2001
Chlorpheniramine	CYP	Flockhart, 2013; Yasuda et al., 2002; Hamelin et al., 1998
Clemastine	CYP	Flockhart, 2013; Hamelin et al., 1998
Desloratadine	CYP, P-gp	Preissner et al., 2010; Chen et al., 2003a
Hydroxyzine	CYP, P-gp	Flockhart, 2013; Hamelin et al., 1998; Kan et al., 2001
Loratadine	CYP, P-gp	Brannan et al., 1995; Ghosal et al., 2009; Chen et al., 2003a
Muscle relaxants
Chlorzoxazone	CYP	Gorski et al., 1997; Flockhart, 2013
Tizanidine	CYP	Granfors et al., 2004; Flockhart, 2013
(Continued)

TABLE 2.  (Continued)

Drug types	Interactions with CYP and/or P-gp	References
Other
Anagrelide	CYP	Wagstaff and Keating, 2006
Chlorpropamide	CYP	Shon et al., 2005
Cisapride	CYP	Desta et al., 2000; Flockhart, 2013
Domperidone	CYP, P-gp	Flockhart, 2013; Ward et al., 2004; Mahar Doan et al., 2002; Faassen et al., 2003; Schinkel et al., 1996
Efavirenz	CYP, P-gp	Flockhart, 2013; Kwara et al., 2008; Nyakutira et al., 2008; Störmer et al., 2002
Glibenclamide	CYP, P-gp	Flockhart, 2013; Lilja et al., 2007; Zhang et al., 2005; Golstein et al., 1999
Loperamide	CYP, P-gp	Kim et al., 2004; Adachi et al., 2001; Wandel et al., 2002; Schinkel et al., 1996; Polli et al., 2001
Metoclopramide	CYP, P-gp	Flockhart, 2013; Desta et al., 2002; Doran et al., 2005
Montelukast	CYP	Flockhart, 2013; Walsky et al., 2005b

FIGURE 1. Thin-layer radiochromatographic profile of methanolic fecal extracts following both intravenous (iv) and oral administration of ¹⁴C-sucralose: (a) 0–24 h fecal sample from a male rat given an iv dose of ¹⁴C-sucralose (2 mg/kg); (b) 0–24 h fecal sample from a male rat maintained on a diet containing 30,000 ppm sucralose for 85 wk before receiving an oral dose of ¹⁴C-sucralose (100 mg/kg). An enlargement of the peak profile is given to the right. (TLC traces from Sims et al., 2000).

TABLE 3.  Percent Differences in Bacterial Counts for Sucralose-Treated Rats Relative to Untreated Control at the End of the 12-wk Treatment Period and at the End of the 12-wk Recovery

	Sucralose dosage delivered daily in Splenda ^a
	Percent change at 1.1 mg/kg ^b ^, ^c	Percent change at 3.3 mg/kg ^b ^, ^c	Percent change at 5.5 mg/kg ^b ^, ^c	Percent change at 11 mg/kg ^b ^, ^c
End of treatment ^d
Total anaerobes	−49.8	−72.2	−73.7	−78.9
Bifidobacteria	−36.9	−71.9	−76.0	−77.7
Lactobacilli	−39.1	−62.8	−66.8	−79.7
Bacteroides	−67.5	−75.6	−74.1	−77.5
Clostridia	—	−47.4	−55.3	−50.5
Total aerobes	—	−51.2	−51.2	−67.8
Enterobacteria	—	—	—	—
End of recovery ^e
Total anaerobes	−53.9	−76.6	−56.7	−48.6
Bifidobacteria	—	−74.6	−61.1	—
Lactobacilli	—	—	—	—
Bacteroides	—	—	—	—
Clostridia	—	—	—	—
Total aerobes	—	—	—	—
Enterobacteria	—	—	—	—
Note. Data from Abou-Donia et al. (2008).
^aRats treated by oral gavage with Splenda containing sucralose doses of 1.1, 3.3, 5.5, and 11 mg/kg/d for 12 wk. Fecal samples were collected weekly over a 24-wk experimental period (12 wk of treatment and 12 wk of recovery).
^bPercent difference in the mean values of bacterial counts of Splenda/sucralose-treated groups relative to untreated controls. Numerical values are significantly different from the control group according to Student's t-test.
^c— Indicates not significantly different from the control group.
^dPercent difference after the 12-wk treatment.
^ePercent difference after 12-wk discontinuation of Splenda/sucralose treatment.

TABLE 4.  Representative Examples of Adverse Effects Reported in Toxicity Studies of Sucralose and Its Hydrolysis Products at High Dosages

Reference	Species (and number of animals affected when given)	Adverse effect
Finn and Lord (2000)	Mouse (1 of 10)	Death during 21 d study: dose (150 mg/kg/d of sucralose hydrolysis products administered by gavage)
	Mouse (2 of 10)	Deaths during 21 d study: dose (1000 mg/kg/d of sucralose hydrolysis products administered by gavage)
	Mouse (increased frequency)	Unkempt coats during 21 d study: dose (500 and 1000 mg/kg/d of sucralose hydrolysis products administered by gavage)
	Mouse (1 of 10)	Slow righting reflex (neurological finding) during 21 d study: dose (500 mg/kg/d of sucralose hydrolysis products administered by gavage)
Mann et al. (2000b)	Mouse	Lower erythrocyte counts in females after 104 wk: dose (3% dietary sucralose); chronic nephropathy in females and chronic inflammation of the liver in males: dose (3.0% dietary sucralose); degeneration of the testicular tubular germinal epithelium: dose (0.3–3.0% dietary sucralose)
Finn and Lord (2000)	Marmoset	Altered salivary responses during second half of 28 d study: dose (1000 mg/kg/d of sucralose and its hydrolysis products administered by gavage)
	Marmoset (2 of 3)	Depressed postural reactions at 13 d into a 28 d study: dose (1000 mg/kg/d of sucralose administered by gavage); reactions reportedly remitted by d 27
	Marmoset (2 of 3)	Depressed postural responses on d 27 of 28 d study: dose (1000 mg/kg/d of sucralose hydrolysis products administered by gavage)
Kille et al. (2000)	Rabbit, pregnant	Gastrointestinal tract disturbances, such as peri-anal soiling, scouring and caecal enlargement: dose (750 to 1000 mg/kg/d of sucralose administered by gavage)
	Rabbit, presumed pregnant (7 of 15)	Mild to severe gastrointestinal distress during d 6 to 19 of gestation: dose (700 mg/kg/d administered by gavage)
Kille et al. (2000); U.S. FDA, 1998	Rabbit, pregnant (12 of 13 deaths occurred in sucralose-treated animals)	Deaths in four groups of 16 to 18 pregnant rabbits: dose (0, 175, 350, and 700 mg/kg/d administered by gavage during d 6 to 19 of gestation); deaths of 11 rabbits (1 control, 4 receiving 175 mg/kg/d group, 2 receiving 350 mg/kg/d group, and 4 receiving 700 mg/kg/d) were not attributed to sucralose by the experimenters although 10 of these 11 deaths occurred during treatment with sucralose. Only two deaths at 700 mg/kg/d were attributed to sucralose by the experimenters.
	Rabbit (4 of 9)	Abortions: dose (700 mg/kg/d administered by gavage)
Goldsmith (2000b)	Rat	Decrease in total leukocyte and lymphocyte counts of females after 4 wk: dose (5.0% dietary sucralose)
		Decrease in alanine aminotransferase (ALT) after 4 wk: dose (5.0% dietary sucralose; also 2.5% in females)
		Decreased serum phosphorus in all male treatment groups after 4 wk: dose (1%, 2.5%, and 5% dietary sucralose)
		Increased urinary excretion of calcium and magnesium in females: dose (5% dietary sucralose)
		Dose-related increase in cecal weight with and without contents: dose (2.5 and 5.0% dietary sucralose)
		Decreases in organ weights including spleen, thymus, and heart after 8 wk: dose (5.0% dietary sucralose)
Mann et al. (2000a)	Rat	Decrease in alanine aminotransferase (ALT) activity after 11, 38, 51, 77 and 103 wk of treatment; dose (3% dietary sucralose)
		Thyroxine levels were decreased in male rats at 11 wk in a dose-dependent manner: dose (0.3% to 3.0% dietary sucralose)
		Higher phosphorus excretion after 77 wk: dose (0.3% to 3.0% dietary sucralose)
		Non-neoplastic findings in females including renal pelvic epithelial hyperplasia, renal pelvic mineralization, and adrenal cortical haemorrhagic degeneration; cataracts in males: dose (3.0% dietary sucralose)
Goldsmith (2000b)	Rat	Increased body weight-relative kidney weights during 28-d study: dose (3000 mg/kg/d by gavage)
		Increased cecum weights during 28-d study: dose (1500 and 3000 mg/kg/d by gavage)
		Elongated or distended caecum during 28-d study: dose (1500 and 3000 mg/kg/d by gavage)
Goldsmith (2000b)	Dog	Lower lymphocyte counts at 3 mo: dose (1% dietary sucralose); lower lymphocyte counts at 6 mo; dose (1% and 3% dietary sucralose); lower lymphocyte counts at 12 mo; dose (0.3% dietary sucralose)

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