SEARCH

SEARCH BY CITATION

Keywords:

  • N-acetyltransferase;
  • carcinogen;
  • cytochrome P450;
  • DNA-adducts;
  • glutathione S-transferase;
  • heterocyclic amines;
  • metabolism;
  • PhIP;
  • prostate

Abstract

Dietary factors appear to be involved in the high incidence of prostate cancer in “Westernized” countries, implicating dietary carcinogens such as heterocyclic amines (HAs) in the initiation of prostate carcinogenesis. We examined 24 human prostate samples with respect to their potential for activation and detoxification of HAs and the presence of DNA adducts formed in vivo. Cytochromes P450 1B1, 3A4 and 3A5 were expressed at low levels (<0.1–6.2 pmol/mg microsomal protein). N-Acetyltransferase (NAT) activities, using p-aminobenzoic acid (NAT1) and sulfamethazine (NAT2) as substrates, were <5–5,500 and <5–43 pmol/min/mg cytosolic protein, respectively. Glutathione S-transferases (GSTs) P1, M2 and M3 were expressed at 0.038–1.284, 0.005–0.126 and 0.010–0.270 μg/mg cytosolic protein, respectively; GSTM1 was expressed in all GSTM1-positive samples (0.012–0.291 μg/mg cytosolic protein); and GSTA1 was expressed at low levels (<0.01–0.11 μg/mg cytosolic protein). Binding of N-hydroxy-PhIP to DNA in vitro occurred primarily by an AcCoA-dependent process (<1–54 pmol/mg/DNA), PAPS- and ATP-dependent binding being <1–7 pmol/mg DNA. In vivo, putative PhIP- or 4-aminobiphenyl-DNA adducts were found in 4 samples (0.4–0.8 adducts/108 bases); putative hydrophobic adducts were found in 6 samples (8–64 adducts/108 bases). Thus, the prostate appears to have low potential for N-hydroxylation of HAs but greater potential for activation of N-hydroxy HAs to genotoxic N-acetoxy esters. The prostate has potential for GSTP1-dependent detoxification of ATP-activated N-hydroxy-PhIP but little potential for detoxification of N-acetoxy-PhIP by GSTA1. However, there were no significant correlations between expression/activities and DNA adducts formed in vitro or in vivo, DNA adducts in vivo possibly reflecting carcinogen exposure. © 2005 Wiley-Liss, Inc.