Anatomical distribution and expression of CYP in humans: Neuropharmacological implications

Abstract

The cytochrome P450 (CYP450) superfamily is responsible for the metabolism of most xenobiotics and pharmacological treatments generally used in clinical settings. Genetic factors as well as environmental determinants acting through fine epigenetic mechanisms modulate the expression of CYP over the lifespan (fetal vs. infancy vs. adult phases) and in diverse organs. In addition, pathological processes might alter the expression of CYP. In this selective review, we sought to summarize the evidence on the expression of CYP focusing on three specific aspects: (a) the anatomical distribution of the expression in body districts relevant in terms of drug pharmacokinetics (liver, gut, and kidney) and pharmacodynamics, focusing for the latter on the brain, since this is the target organ of psychopharmacological agents; (b) the patterns of expression during developmental phases; and (c) the expression of CYP450 enzymes during pathological processes such as cancer. We showed that CYP isoforms show distinct patterns of expression depending on the body district and the specific developmental phases. Of particular relevance for neuropsychopharmacology is the complex regulatory mechanisms that significantly modulate the complexity of the pharmacokinetic regulation, including the concentration of specific CYP isoforms in distinct areas of the brain, where they could greatly affect local substrate and metabolite concentrations of drugs.

Conversion of five proluciferin esters by human cytochrome P450 enzymes

“…Their substrate scope is truly vast, encompassing a range of fatty acids, eicosanoids, steroids and seco-steroids, drugs of many different classes, and other xenobiotics such as environmental toxins or foodderived chemicals. [7,11] A total of more than a hundred X-ray structures of about two dozen human CYP enzymes are known and they display a large variation in the volume of their active sites (from less than 200 Å 3 to at least 2000 Å 3 ); [12] in addition, some P450s are more flexible and others are quite rigid. [1,13,14] These properties are reflected in the substrate selectivity profiles, which vary from narrow to very broad; moreover, there is significant overlap in substrate profiles, especially between the more promiscuous enzymes.…”

A Comparison of Calcium Aggregation and Ultracentrifugation Methods for the Preparation of Rat Brain Microsomes for Drug Metabolism Studies

“…The cytochrome P450 (P450) enzymes are responsible for the metabolism of most xenobiotics and endogenous compounds. In addition to the liver, which is the main organ with the highest P450 content, P450 enzymes are also expressed in extrahepatic tissues such as the brain [1]. The distribution of P450 enzymes in different brain regions is not uniform, with the highest P450 content found in the brain stem and cerebellum, while the striatum and hippocampus reportedly contain the lowest P450 content [2].…”

“…Although the total P450 content in the brain is only 0.5%-2% of that in the liver [3,4], brain P450 enzymes are concentrated in specific cells and important brain regions, such as the blood-brain barrier [5]. There-DuBois/Amirrad/Mehvar Pharmacology 2021;106:687-692 688 DOI: 10.1159/000519667 fore, brain P450 may significantly impact the pharmacologic activities or toxicity of the centrally acting drugs and toxins [1,[3][4][5].…”

Personalized treatments in neuropsychiatric disorders

“…One article investigated biological markers of response to noninvasive brain stimulation in Autistic patients (Robinson‐Agramonte et al, 2021), while two articles focused on neurodegenerative disorders, specifically on Parkinson's disease (Cacabelos et al, 2021) and multiple sclerosis (Sánchez et al, 2021). Finally, one article focused on the relevance for the pharmacology of neuropsychiatric disorders of the expression and localization of cytochrome genes in human tissues (Fanni et al, 2021).…”

“…Finally, Fanni et al (2021) performed a selective review presenting an historical overview, applications, and future perspectives on the functioning, regulation, and expression of members of the CYP p450 superfamily. The article also summarized findings on the body distribution of CYP isoenzymes, with a specific focus on the liver, gut, kidney, and the central nervous system (CNS).…”