Role of Metabolic Enzymes P450 (CYP) on Activating Procarcinogen and their Polymorphisms on the Risk of Cancers

Abstract

Cytochrome P450 (CYP450) enzymes are the most important metabolizing enzyme family exists among all organs. Apart from their role in the deactivation of most endogenous compounds and xenobiotics, they also mediate most procarcinogens oxidation to ultimate carcinogens. There are several modes of CYP450s activation of procarcinogens. 1) Formation of epoxide and diol-epoxides intermediates, such as CYP1A1 and CYP1B1 mediates PAHs oxidation to epoxide intermediates; 2) Formation of diazonium ions, such as CYP2A6, CYP2A13 and CYP2E1 mediates activation of most nitrosamines to unstable metabolites, which can rearrange to give diazonium ions. 3) Formation of reactive semiquinones and quinines, such as CYP1A1 and CYP1B1 transformation of estradiol to catechol estrogens, subsequently formation semiquinones; 4) Formation of toxic O-esterification, such as CYP1A1 and CYP1A2 metabolizes PhIP to N(2)-acetoxy-PhIP and N(2)-sulfonyloxy-PhIP, which are carcinogenic metabolites. 5) Formation of free radical, such as CYP2E1 is involved in activation tetrachloromethane to free radicals. While for CYP2B6 and CYP2D6, only a minor role has been found in procarcinogens activation. In addition, as the gene polymorphisms reflected, the polymorphisms of CYP1A1 (-3801T/C and -4889A/G), CYP1A2 (- 163C/A and -2467T/delT), CYP1B1 (-48G/C, -119G/T and -432G/C), CYP2E1 (-1293G/C and -1053 C/T) have been associated with an increased risk of lung cancer. The polymorphisms CYP1A1 (-3801T/C and -4889A/G), and CYP2E1 (PstI/Rsa and 9-bp insertion) have an association with higher risk colon cancers, whereas CYP1A2 (-163C/A and -3860G/A) polymorphism is found to be among the protective factors. The polymorphisms CYP1A1 (-3801T/C and -4889A/G), CYP1B1 -432G/C, CYP2B6 (-516G/T and -785A/G) may increase the risk of breast cancer. In conclusion, CYP1A1, CYP1A2, CYP1B1, CYP2A6, and CYP2E1 are responsible for most of the procarcinogens activation, and their gene polymorphisms are associated with the risk of cancers.

Associations betweenCYP1A1rs1048943 A > G and rs4646903 T > C genetic variations and colorectal cancer risk: Proof from 26 case-control studies

“…Because the main role of this enzyme is to metabolize environmental carcinogens, such as PAHs, heterocyclic amines, aflatoxin B1 and estrogen [37], variations within CYP1A1 gene may induce the occurrence of CRC. Currently, a widely accepted paradigm for CYP1A1 enzyme mediated carcinogens activation is that CYP1A1 metabolizes polycyclic aromatic hydrocarbons to reactive epoxide intermediates, which could covalently bind to DNA and then induce tumors [38]. …”

Hepatotoxicity in Rats Induced by Aqueous Extract of Polygoni Multiflori Radix, Root of Polygonum multiflorum Related to the Activity Inhibition of CYP1A2 or CYP2E1

“…Rat serum ALT and AST levels significantly increased in the group with the administration of PMR and CYP1A2 or CYP2E1 inhibitor compared with all control groups at 1 d, 3 d, 5 d, 7 d, and 22 d, but no greater than twofold, which suggested that PMR related hepatotoxicity that happened in clinic might be due to some people with lower activities of CYP1A2 or CYP2E1 from genetic polymorphism [22, 23]. Actually, there was a clinical report which suggested that PMR induced hepatotoxicity may relate to low activity of CYP1A2 [28].…”

“…CYP1A2 and CYP2E1 mainly exist in the liver, accounting for 13% and 7% of total CYP450 enzymes, respectively [21]. In addition, CYP1A2 and CYP2E1 exhibit genetic polymorphism in the population [22, 23]. At least 23 allele genes of CYP1A2 have been found so far, and the major mutants are CYP1A2 ∗ 1C, CYP1A2 ∗ 1D, CYP1A2 ∗ 1F, CYP1A2 ∗ 1K, CYP1A2 ∗ 7, and CYP1A2 ∗ 11.…”

Roles of defective ALDH2 polymorphism on liver protection and cancer development

“…Similarly, Ishikawa and colleagues [51] showed that subjects carrying the ALDH2*2 allele who consumed ethanol more than three times per week had greater DNA damage, as reflected by an increased micronuclei frequency. Furthermore, cytochrome P450 (CYP2E1), which is known to form reactive oxygen species [52] and enhance pro-carcinogen activation [53], is upregulated in Aldh2 knockout mice, and is further induced by ethanol administration [54]. As such, ALDH2*2 has the potential to promote the risk of cancers induced by alcohol consumption (Fig.…”