Metabolic Activation of the Cooked Meat Carcinogen 2-Amino-1-Methyl-6-Phenylimidazo[4, 5-b]Pyridine in Human Prostate. (27th March 2018)

• Record Type: Journal Article
• Authors: Bellamri, Medjda; Xiao, Shun; Murugan, Paari; Weight, Christopher J; Turesky, Robert J
• Is Part Of: Toxicological sciences. Volume 163:Number 2(2018)
• Page Start: 543
• Page End: 556
• Publication Date: 2018-03-27
• Subjects: prostate cancer -- heterocyclic aromatic amines -- 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine -- DNA adduct -- metabolic activation; Toxicology -- Periodicals; Toxicology -- Periodicals; Toxicology; Periodicals; 615.9
• DOI: 10.1093/toxsci/kfy060
• Languages: English
• ISSNs: 1096-6080

Abstract

Abstract: 2-Amino-1-methyl-6-phenylimidazo[4, 5- b ]pyridine (PhIP), an heterocyclic aromatic amine (HAA) formed in cooked meat, is a rodent and possible human prostate carcinogen. Recently, we identified DNA adducts of PhIP in the genome of prostate cancer patients, but adducts of 2-amino-3, 8-dimethylmidazo[4, 5- f ]quinoxaline (MeIQx) and 2-amino-9 H -pyrido[2, 3- b ]indole (AαC), other prominent HAAs formed in cooked meats, were not detected. We have investigated the bioactivation of HAAs by Phase I and II enzymes in the human prostate (LNCaP) cell line using cytotoxicity and DNA adducts as endpoints. PhIP, MeIQx, and 2-amino-3-methylimidazo[4, 5- f ]quinoline, another HAA found in cooked meats, were poorly bioactivated and not toxic. The synthetic genotoxic N-hydroxylated-HAAs were also assayed in LNCaP cells with Phase II enzyme inhibitors. Notably, 2-hydroxy-amino-1-methyl-6-phenylimidazo[4, 5- b ]pyridine (HONH-PhIP), but not other HONH-HAAs, induced cytotoxicity. Moreover, PhIP-DNA adduct formation was 20-fold greater than adducts formed with other HONH-HAAs. Pretreatment of LNCaP cells with mefenamic acid, a specific inhibitor of sulfotransferase (SULT1A1), decreased PhIP-DNA adducts by 25%, whereas ( Z )-5-(2′-hydroxybenzylidene)-2-thioxothiazolidin-4-one and pentachlorophenol, inhibitors of SULTs and N-acetyltransferases (NATs), decreased the PhIP-DNA adduct levels by 75%. NATs in cytosolic fractions of LNCaP cells and human prostate catalyzed DNA binding of HONH-PhIP by up to 100-fold greater levels than for SULT and kinase activities. Recombinant NAT2 is catalytically superior to recombinant NAT1 in the bioactivation of HONH-PhIP; however, the extremely low levels of NAT2 activity in prostate suggest that NAT1 may be the major isoform involved in PhIP-DNA damage. Thus, the high susceptibility of LNCaP cells recapitulates the DNA-damaging effect of HONH-PhIP in rodent and human prostate.