Impact of physiological, pathological and environmental factors on the expression and activity of human cytochrome P450 2D6 and implications in precision medicine

Abstract

With only 1.3-4.3% in total hepatic CYP content, human CYP2D6 can metabolize more than 160 drugs. It is a highly polymorphic enzyme and subject to marked inhibition by a number of drugs, causing a large interindividual variability in drug clearance and drug response and drug-drug interactions. The expression and activity of CYP2D6 are regulated by a number of physiological, pathological and environmental factors at transcriptional, post-transcriptional, translational and epigenetic levels. DNA hypermethylation and histone modifications can repress the expression of CYP2D6. Hepatocyte nuclear factor-4α binds to a directly repeated element in the promoter of CYP2D6 and thus regulates the expression of CYP2D6. Small heterodimer partner represses hepatocyte nuclear factor-4α-mediated transactivation of CYP2D6. GW4064, a farnesoid X receptor agonist, decreases hepatic CYP2D6 expression and activity while increasing small heterodimer partner expression and its recruitment to the CYP2D6 promoter. The genotypes are key determinants of interindividual variability in CYP2D6 expression and activity. Recent genome-wide association studies have identified a large number of genes that can regulate CYP2D6. Pregnancy induces CYP2D6 via unknown mechanisms. Renal or liver diseases, smoking and alcohol use have minor to moderate effects only on CYP2D6 activity. Unlike CYP1 and 3 and other CYP2 members, CYP2D6 is resistant to typical inducers such as rifampin, phenobarbital and dexamethasone. Post-translational modifications such as phosphorylation of CYP2D6 Ser135 have been observed, but the functional impact is unknown. Further functional and validation studies are needed to clarify the role of nuclear receptors, epigenetic factors and other factors in the regulation of CYP2D6.

The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone

“…For instance, men have a lower CYP3A4 activity; while women have lower activity of other CYPs including CYP2E1 and 1A2 (Cotreau et al 2005; Scandlyn et al 2008; Waxman and Holloway 2009). Autoimmune hepatitis, chronic renal failure, and diabetes have been reported to affect the metabolism of drugs by inhibiting key enzymes in the liver, such as CYP2D6, 3A4/5, and 1A2 (He et al 2015). It is particularly important to note that CYP3A4, 3A5 and 2D6 can be inhibited by a number of drugs, foods, and dietary supplements.…”

Collaborative Counseling Considerations for Pharmacogenomic Tests

“…However, even relatives with the same variant in a common PGx gene such as CYP2D6 may metabolize and excrete associated drugs differently due to variable health factors (e.g., liver or renal function, size, etc. ), lifestyle characteristics, other drugs, and/or other genetic factors . If findings may be of interest to relatives, PGx testing is suggested for any family members who desire the most definitive information on their drug metabolism status.…”

Gene-environment interactions as the basis of health formation

“…В гене CYP2D6 известны SNP, частоты аллелей по ко-торым показывают существенную этнотерриториальную вариабельность [3]. Для этого гена доказана регуляция на транскрипционном, посттранскрипционном, трансля-ционном и эпигенетическом уровнях, при этом уровень экспрессии гена CYP2D6 и активность кодируемого им фермента зависят от функционального состояния орга-низма и экологических условий [60]. Все это приводит к значительной межиндивидуальной изменчивости в от-ношении ответа на лекарственные препараты, их взаи-модействия и побочных эффектов.…”