Polymorphism of human cytochrome P450 enzymes and its clinical impact

Abstract

Pharmacogenetics is the study of how interindividual variations in the DNA sequence of specific genes affect drug response. This article highlights current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) to understand the large interindividual variability in drug clearance and responses in clinical practice. The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant enzyme that demonstrates multiple genetic variants with a potentially functional impact on the efficacy and adverse effects of drugs that are mainly eliminated by this enzyme. Studies into the CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and *3 alleles. Extensive polymorphism also occurs in other CYP genes, such as CYP1A1, 2A6, 2A13, 2C8, 3A4, and 3A5. Since several of these CYPs (e.g., CYP1A1 and 1A2) play a role in the bioactivation of many procarcinogens, polymorphisms of these enzymes may contribute to the variable susceptibility to carcinogenesis. The distribution of the common variant alleles of CYP genes varies among different ethnic populations. Pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and currently available drugs. Further studies are warranted to explore the gene-dose, gene-concentration, and gene-response relationships for these important drug-metabolizing CYPs.

Allele Frequency Distributions of the Drug Metabolizer Genes <i>CYP2C9*2</i>, <i>CYP2C9*3</i>, and <i>CYP2C19*17</i> in the Buginese Population of Indonesia

“…The data showed a similar general trend as that seen for other Asian groups, namely, a negligible frequency of CYP2C9*2, and the presence of the CYP2C9*3 allele at a frequency between 2%-5% [9,13,14]. This observation is in line with the report that the CYP2C9*2 allele is primarily restricted to European, Middle Eastern and Central/South Asian populations, but is absent or found at very low frequencies in other geographic regions (Africa, East Asia, Oceania and America).…”

Molecular Targets of Cannabidiol in Neurological Disorders

“…In eukaryotes, it is mainly found in the endoplasmic reticulum and mitochondria where it maintains homeostatic control of lipophilic endogenous compounds and the detoxification of lipophilic xenobiotic compounds by oxidation, making them more water soluble, and is thus the main component of phase 1 metabolism. It is highly diverse, with many different isoforms [56]. CBD inhibits human recombinant CYP2C19 using a mixed inhibition mechanism (Ki = 0.793 μM) [57].…”

Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting

“…Specifically, we evaluated quantitatively the expression of the five key CYPs, CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, which account for 60% of human drug oxidation (38). Among the five CYPs, the hiPSC-HPCs in 3D triculture model showed a significantly higher expression of CYP3A4, which is the most common CYP enzyme and estimated to be involved in the metabolism of approximately half the currently used drugs (Fig.…”