Immunohistochemical Detection of Carcinogen‐DNA Adducts in Normal Human Prostate Tissues Transplanted into the Subcutis of Athymic Nude Mice: Results with 2‐Amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) and 3,2′‐Dimethyl‐4‐aminobiphenyl (DMAB) and Relation to Cytochrome P450s and N‐Acetyltransferase Activity

Application of a Micropatterned Cocultured Hepatocyte System To Predict Preclinical and Human-Specific Drug Metabolism

“…Upon incubations of procainamide (6) in human fibroblast cells, the N-acetylprocainamide metabolite (6a) was produced in qualitatively similar amounts after a 7-day incubation period, as compared with the dog MPCC hepatocytes, confirming our hypothesis (data not shown). The other compounds in our study were not tested in fibroblasts, and we cannot exclude that fibroblasts may form some of the minor metabolites; however, fibroblasts are not known to possess significant phase 1 (i.e., cytochrome P450, AO) or phase II (i.e., NAT, UGT) enzymatic activity (Cui et al, 2000;Moriwaki et al, 2001;Du et al, 2014). Overall, the MPCC hepatocyte system recapitulated in vivo metabolism data when controlled for the stromal cell component, which should be monitored in dog specifically.…”

A Prospective Study of Meat and Meat Mutagens and Prostate Cancer Risk

“…Human prostate tissue is known to express CYP and NAT enzymes (10)(11)(12), which metabolically activate HCAs, leading to increased DNA adduct levels in response to PhIP (33). In addition, treatment of primary cell cultures from human prostate tissue with PhIP results in dose-dependent genotoxic damage (34,35).…”

Association of SULT1A1 Phenotype and Genotype with Prostate Cancer Risk in African-Americans and Caucasians

“…Studies by Kaderlik et al (46) suggests that N-hydroxy-PhIP produced in the liver is stable enough to be carried via the circulation to target tissues such as prostate, where subsequent metabolism can generate DNA-binding species. Human prostate tissue has been shown to metabolically activate N-hydroxy-PhIP to DNA-binding species (47), and transplantation of human prostate into athymic mice followed by exposure to PhIP resulted in PhIP-DNA adducts in ϳ95% of samples (48). Whereas these studies examined the N-acetyltransferase pathway of HCA activation, heterologous expression of human N-acetyltransferase and SULT enzymes in Salmonella typhimurium and mutagenicity testing of HCAs suggested that N-OH-PhIP was activated specifically by SULT1A1 (13).…”