Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

Abstract

The polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. Genotyping for CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk.

Four Polymorphisms in the Cytochrome P450 1A2 (CYP1A2) Gene and Lung Cancer Risk: a Meta-analysis

“…Thus, genetic mutations in the CYP1A2 gene are considered to be associated with increased CYP1A2 activity and may be linked to the carcinogenic process (Bozina et al, 2009). CYP1A2 have been reported to be associated with different kinds of cancer risk such as Cholangiocarcinoma, lung cancer (Kukongviriyapan., 2012;Deng et al, 2013).…”

Application of Precision-Cut Rat Liver Slice to Study the Influence of Monocrotaline, <i>Tussilago farfara</i> Alkaloids on the Expression of Cytochrome P450 Enzymes

“…Human genome sequence has revealed about 107 human P450 genes: 59 active and about 48 pseudogenes, and mainly 10 genes encode protease involved in drug metabolism, in which the most important enzymes for drug metabolism are CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and about 34% of drug metabolism are catalyzed by CYP3A4. The most important isoforms responsible for the biotransformation of chemicals and especially for the metabolic activation of pre-carcinogens are CYP1A, CYP1A2, CYP1B1, CYP2A6, CYP2E1 and CYP3A4, and more than 70 different chemicals with diverse structures are metabolised by CYP2E1 [27] [28]. CYP2B is mainly existed in the form of CYP2B1 in SD rats [29], the induction of CYP2B by Phenobarbital has been studied in rat liver slices [1].…”

Polymorphisms of Estrogen Biosynthesis and Metabolizing Genes in Egyptian Women With Breast Cancer.

“…These include the 16 alpha hydroxylation pathway, the pathway of 2-hydroxylation, the pathway of 4-hydroxylation through redox cycling, besides 4-hydroxyestradiolquinone-adenine/guanine adduct depurination pathway (yue, et al; 2013). Single nucleotide polymorphisms (SNPs) in genes of estrogen biosynthesis and metabolism might have an effect on levels of circulating estrogen and affect the susceptibility of breast cancer (Bozina, et al;2009). The human CYP17 gene found on 10q24.3 chromosome (Fan, et al;1992), encodes for cytochrome p450c17A that mediates activities vital for the endogenous steroid hormones production, such as estrogen and androgen (Miller, 1998).…”