Polymorphism of Drug-Metabolizing Enzymes in Relation to Individual Susceptibility to Industrial Chemicals.

Abstract

Polymorphism and the induction/inhibition of drug-metabolizing enzymes, such as cytochrome P450, aldehyde dehydrogenase (ALDH), glutathione S-transferase (GST), Nacetyltransferase (NAT), and NAD(P)H-quinone oxidoreductase (NQO1), were reviewed in relation to susceptibility to disease and to inter-individual difference in biological monitorings. A number of genetic and acquired factors can influence the susceptibility of an individual to chemicals, creating a so-called predisposition. Most cases in which genetic factors were present resulted from polymorphism of drug-metabolizing enzymes. However, conflicting reports have appeared on the relationship between polymorphism and risk of disease; in some cases, biologically plausible mechanisms linking genotypes and disease are not yet in evidence. Current findings based on biological monitoring of chemicals are insufficient to evaluate the relationship between genetic polymorphism and acquired risk when exposure has occurred in an occupational area. Investigation of such situations has generated data implicating GSTT1, GSTM1, NAT2, and NQO1 polymorphisms in biological monitoring of some chemicals; the ALDH2 polymorphism is the likely link between the genotype and the metabolism of low molecular aliphatic aldehydes. Although this polymorphism is limited in the case of Japanese as well as other Asian subjects, the inhibitors of ALDH2 activity such as trichloroethylene may produce a false polymorphism of this gene. As to the effect of factors influencing acquired predisposition, such as ethanol intake, intake of low carbohydrate diet or diabetes, corroborative epidemiological studies may be further required.

Cytochrome P450 2E1 variable number tandem repeat polymorphisms and health risks: A genotype-phenotype study in cancers associated with drinking and/or smoking

“…Polymorphisms in this gene can create differences in the ability to metabolize, detoxify or activate a number of substances. This ability can generate certain reactive substances which may consequently increase the risk of deve loping serious diseases, such as tumours (7,8,14,27). The VNTR polymorphism in the 5'-flanking region of the CYP2E1 gene has previously been described (18).…”

“…CYP2E1 has also been shown to be involved in the metabolism of more than 80 low-molecular hydrophobic toxicologically dangerous compounds and contributes to the activation of a number of pro-carcinogens and drugs into highly reactive metabolites (6,7). Specifically, CYP2E1 activates N-nitrosamines contained in tobacco smoke and foodstuffs (8)(9)(10) and several industrial (11) and endogenous carcinogens (12,13); moreover, it is capable of reducing mole cular oxygen to highly reactive compounds, such as superoxide anion radical (О 2 -), singlet oxygen ( 1 О 2 ), hydrogen peroxide (H 2 O 2 ) and hydroxyl radical (ОН · ) leading to DNA damage and carcinogenesis (14,15).…”

Research Article Synergic effect of oral contraceptives, GSTP1 polymorphisms, and high-risk HPV infection in development of cervical lesions.

“…In MAPK kinase pathway, GSTP1 suppresses MEKK1 activity (Zhao et al, 2006). Genetic variations in GSTP1 sequences may be relevant in cancer susceptibility because it may promote differential metabolism of carcinogen and anti-carcinogen compounds (Nakajima and Aoyama, 2000).…”

Disinfection by-products exposure and intra-uterine growth restriction: Do genetic polymorphisms of CYP2E1or deletion of GSTM1 or GSTT1 modify the association?

“…As a matter of fact, the GSTT1 enzyme is responsible for increasing toxic properties of some chemicals (Nakajima and Aoyama 2000) and essential in the activation of the mutagen activity of brominated THMs (Landi et al 1999). Moreover, GSTT1 polymorphisms were involved in the increased associations between THM and bladder cancer in Spain (Cantor et al 2010).…”