Effects of genetic polymorphisms of MDR1, FMO3 and CYP1A2 on susceptibility to colorectal cancer in Koreans

Abstract

The aim of the present study was to evaluate the effects on the susceptibility to colorectal cancer (CRC) of genetic polymorphisms in P-glycoprotein (PGP) and the metabolic enzymes cytochrome P450 1A2 (CYP1A2) and flavin-containing monooxygenase 3 (FMO3). We analyzed five single-nucleotide polymorphisms (SNP) in 93 cancer-free volunteers and 111 patients with CRC: one common genetic variant of the PGP-encoding MDR1 gene and four SNP in genes for metabolic enzymes (two SNP in FMO3 and two SNP in CYP1A2). The genotypes and allele frequencies of the MDR1/C3435T, FMO3/G488A, FMO3/A923G and CYP1A2/G-3860 A polymorphisms were not significantly different in cancerfree subjects and CRC patients. However, a significant association was found between the CYP1A2/A-163C polymorphism and the risk of CRC, particularly in elderly (>55 years) subjects and smokers. A phenotyping study in normal smokers showed that the CYP1A2 activity of subjects with the CYP1A2/− − − −163 AA genotype was significantly lower than that of subjects carrying the CYP1A2 (1-6) The carcinogens that cause the development of CRC enter the body as (pro)carcinogens via transporters, (7)(8)(9) and are activated to carcinogens or eliminated by various enzymes.(10) These toxicokinetic-related proteins are also controlled by our genetic background (e.g. by genetic polymorphisms). In considering the effects of genetic polymorphisms on the toxicokinetic profiles of xenobiotics, particularly (pro) carcinogens, we must evaluate the combined effects of genetic polymorphisms in both transporters and metabolic enzymes.To date, numerous studies have been conducted to correlate the genetic polymorphisms of single proteins and the risk of disease development or progression. In particular, genetic polymorphisms in drug metabolizing enzymes, such as the cytochrome P450 1 (CYP1A) family, (11,12) glutathione Stransferases, (13) N-acetyltransferases (14) and UDP-glucuronosyltransferases, (15) are the most well-known and important genetic factors in the development of CRC. Flavin-containing monooxygenase 3 (FMO3) is one of the major hepatic metabolic enzymes that catalyze the NADPH-dependent attachment of molecular oxygen to endogenous and foreign chemicals containing nucleophilic N, S and P heteroatoms. There are few studies of the relationship between FMO3 activity and carcinogenesis. A drug transporter, P-glycoprotein (PGP), is a recognized gatekeeper that limits the accumulation of xenobiotics in the body by facilitating ATPconsuming efflux. Recently, studies of the relationship between MDR1 polymorphisms and disease susceptibility have been conducted. (16,17) However, there has been no report of the relationship between the combined genetic polymorphisms of drug transporters and metabolic enzymes and CRC development.Against this background, we analyzed the common genetic polymorphisms in the genes for the drug transporter MDR1 and the metabolic enzymes CYP1A2 and FMO3, and attempted to elucidate the association between these polymorphisms and sporadic CRC in Koreans. We a...

Associations of ABCB1 and XPC Genetic Polymorphisms with Susceptibility to Colorectal Cancer and Therapeutic Prognosis in a Chinese Population

“…In agreement with our results, Andersen and co-workers found that carriers of C allele of the C3435T polymorphism had an increased risk of CRC in Norwegian Caucasian population (Andersen et al, 2009). On the contrary, in an Iran population investigation, T allele of the ABCB1 C3435T polymorphism showed significantly increased risk of CRC (Khedri et al, 2011), while others did not find any statistically significant associations (Bae et al, 2006;Samanian et al, 2011). Regarding ABCB1 G2677T/A genotypes and risk for CRC, we did not find any correlation between CRC risk and the investigated G2677T/A genotypes, likewise, De Iudicibus et al found no relation between ABCB1 G2677T/A polymorphism and CRC patients (De Iudicibus et al, 2008).These data suggest that the role of the ABCB1 polymorphisms in cancer risk may vary with ethnicity, a possibility that warrants further investigation.…”

“…However, Andersen et al reported that carriers of the variant allele of MDR1 C3435T had a lower risk of CRC than homozygous C allele carriers (Andersen et al, 2009). Moreover, Bae et al found no association of the ABCB1 C3435T polymorphism with CRCs in Koreans (Bae et al, 2006). In addition, the G2677T polymorphism was reported to be significantly associated with CRCs with high microsatellite instability (Samanian et al, 2011).…”

Genetic Polymorphisms of Human Flavin-Containing Monooxygenase 3: Implications for Drug Metabolism and Clinical Perspectives

“…For example, certain FMO3 polymorphisms are not associated with common diseases such as colorectal cancer and hypertension [68,69]. This is one gray area illustrative of the amount of additional research needed to establish the significance of FMO3 polymorphisms in human diseases and their management.…”

Cytochrome b5 shifts oxidation of the anticancer drug ellipticine by cytochromes P450 1A1 and 1A2 from its detoxication to activation, thereby modulating its pharmacological efficacy

“…CYP1A1*2A, CYP1A1*2B and CYP1A1*4 polymorphisms have been found that might be associated with cancers of lung, esophagus or breast and with acute myeloid leukemia [54][55][56][57], while the CYP1A2*1F polymorphism might be associated with an increased risk of colorectal cancer [52]. In addition, the CYP1A2*1C allele has been associated with decreased caffeine 3-demethylation [58], and the CYP1A2*1F allele was correlated to increased activity [59,60].…”

“…Moreover, the CYP1A1 and CYP1A2 genes are polymorphic [39,49,52,53]. CYP1A1*2A, CYP1A1*2B and CYP1A1*4 polymorphisms have been found that might be associated with cancers of lung, esophagus or breast and with acute myeloid leukemia [54][55][56][57], while the CYP1A2*1F polymorphism might be associated with an increased risk of colorectal cancer [52].…”