The regulation of liver cytochrome P450 expression and activity by the brain serotonergic system in different experimental models

ABSTRACT

Introduction: Cytochrome P450 (CYP) metabolizes vital endogenous (steroids, vitamins) and exogenous (drugs, toxins) substrates. Studies of the last decade have revealed that the brain dopaminergic and noradrenergic systems are involved in the regulation of CYP. Recent research indicates that the brain serotonergic system is also engaged in its regulation.

Areas covered: This review focuses on the role of the brain serotonergic system in the regulation of liver CYP expression. It shows the effect of lesion and activation of the serotonergic system after peripheral or intracerebral injections of neurotoxins, serotonin precursor, or serotonin (5-HT) receptor agonists. An opposite role of the hypothalamic paraventricular and arcuate nuclei and 5-HT receptors present therein in the regulation of CYP is described. The engagement of those nuclei in the neuroendocrine regulation of CYP by hypothalamic releasing or inhibiting hormones, pituitary hormones, and peripheral gland hormones are shown.

Expert opinion: In general, the brain serotonergic system negatively regulates liver cytochrome P450. However, the effects of serotonergic agents on the enzyme expression depend on their mechanism of action, the route of administration (intracerebral/peripheral), as well as on local intracerebral site of injection and 5-HT receptor-subtypes present therein.

KEYWORDS:

• Brain
• serotonin
• serotonergic receptors
• hormones
• liver
• cytochrome P450 regulation

Article highlights

• The brain serotonergic system negatively regulates liver cytochrome P450 (CYP) via neuroendocrine mechanisms.

• Hypothalamic paraventricular and arcuate nuclei and 5-HT receptors present therein exert opposite effects on the regulation of CYP (negatively by 5-HT1A and positively by 5-HT2C, respectively).

• The effects of serotonergic agents on liver cytochrome P450 expression depend on their mechanism of action and the route of administration (intracerebral/peripheral).

• The effects of intracerebrally injected serotonergic agents on CYP expression depend on the local site of injection and 5-HT receptor-subtypes present therein.

• Cytochrome P450 enzymes regulated by the brain serotonergic system (CYP1A, 2B, 2C, 3A) metabolize vital endogenous (steroids) and exogenous (drugs, toxins) substrates.

This box summarizes the key points contained in the article.

Acknowledgments

The authors express their thanks to all the colleagues from the Department of Pharmacokinetics and Drug Metabolism, Maj Institute of Pharmacology, Polish Academy of Sciences, who collaborated with them in obtaining the results described in this review article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was financially supported by statutory funds from the Maj Institute of Pharmacology, Polish Academy of Sciences (Kraków, Poland).