The role of human glutathione S-transferases (hGSTs) in the detoxification of the food-derived carcinogen metabolite N-acetoxy-PhIP, and the effect of a polymorphism in hGSTA1 on colorectal cancer risk.
Food-derived heterocyclic amines (HCAs), particularly 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), are implicated in the etiology of human colorectal cancer (CRC) via a process of N-oxidation followed by O-acetylation or O-sulfation to form electrophilic metabolites that react with DNA. Glutathione S-transferases (GSTs) detoxify activated carcinogen metabolites by catalysis of their reaction with GSH. However, among HCAs, only N-acetoxy-PhIP has been shown to be a substrate for the GSTs. By using a competitive DNA-binding assay, we confirm that hGSTA1-1 is an efficient catalyst of the detoxification of N-acetoxy-PhIP. Further, we show that hGSTs A2-2, P1-1, M1-1, T1-1 and T2-2 appear to have low activity towards N-acetoxy-PhIP, and that hGSTs A4-4, M2-2, M4-4 and Z1-1 appear to have no activity towards N-acetoxy-PhIP. A genetic polymorphism in the 5'-regulatory sequence of hGSTA1 has been shown to correlate with the relative and absolute levels of expression of GSTA1/GSTA2 in human liver. Examination of hGSTA1 allele frequency in 100 Caucasian CRC patients and 226 Caucasian controls demonstrated a significant over-representation of the homozygous hGSTA1*B genotype among cases compared to controls (24.0 and 13.7%, respectively, P=0.04). This corresponds to an odds ratio for risk of CRC of 2.0 (95% CI 1.0-3.7) when comparing homozygous hGSTA1*B individuals with all other genotypes. Thus, individuals who are homozygous hGSTA1*B, and who would be predicted to have the lowest levels of hGSTA1 expression in their livers, appear to be at risk of developing CRC, possibly as a result of inefficient hepatic detoxification of N-acetoxy-PhIP.
Coles
B
B
Division of Molecular Epidemiology, National Center for Toxicological Research (HFT 100), 3900 NCTR Road, Jefferson, AR 72079, USA. bcoles@nctr.fda.gov
Nowell
S A
SA
MacLeod
S L
SL
Sweeney
C
C
Lang
N P
NP
Kadlubar
F F
FF
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002273:Carcinogens / Q000378:metabolism; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D005260:Female; D005502:Food; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009153:Mutagens / Q000378:metabolism; D009928:Organ Specificity; D011110:Polymorphism, Genetic; D011725:Pyridines / Q000378:metabolism / Q000493:pharmacokinetics*; D044465:White People
C096092:2-(acetoxyamino)-1-methyl-6-phenylimidazo(4,5-b)pyridine; D002273:Carcinogens; D007093:Imidazoles; D007527:Isoenzymes; D009153:Mutagens; D011725:Pyridines; D004247:DNA; D005982:Glutathione Transferase