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

Mutat Res. 2001 Oct 1;482(1-2):3-10. doi: 10.1016/s0027-5107(01)00187-7.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Carcinogens / metabolism
  • Case-Control Studies
  • Colorectal Neoplasms / etiology
  • Colorectal Neoplasms / genetics*
  • DNA / metabolism
  • European Continental Ancestry Group
  • Female
  • Food
  • Genetic Predisposition to Disease
  • Glutathione Transferase / genetics*
  • Glutathione Transferase / metabolism*
  • Humans
  • Imidazoles / metabolism
  • Imidazoles / pharmacokinetics*
  • Inactivation, Metabolic
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Male
  • Middle Aged
  • Mutagens / metabolism
  • Organ Specificity
  • Polymorphism, Genetic*
  • Pyridines / metabolism
  • Pyridines / pharmacokinetics*

Substances

  • 2-(acetoxyamino)-1-methyl-6-phenylimidazo(4,5-b)pyridine
  • Carcinogens
  • Imidazoles
  • Isoenzymes
  • Mutagens
  • Pyridines
  • DNA
  • Glutathione Transferase