Expression of cytochromes P450 and glutathione S-transferases in human prostate, and the potential for activation of heterocyclic amine carcinogens via acetyl-coA-, PAPS- and ATP-dependent pathways.
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 microg/mg cytosolic protein, respectively; GSTM1 was expressed in all GSTM1-positive samples (0.012-0.291 microg/mg cytosolic protein); and GSTA1 was expressed at low levels (<0.01-0.11 microg/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/10(8) bases); putative hydrophobic adducts were found in 6 samples (8-64 adducts/10(8) 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.
Di Paolo
Oscar A
OA
Division of Pharmacogenomics and Molecular Epidemiology, National Center for Toxicological Research, Jefferson, AR 72079-9502, USA.
Teitel
Candee H
CH
Nowell
Susan
S
Coles
Brian F
BF
Kadlubar
Fred F
FF
D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000368:Aged; D000369:Aged, 80 and over; D047068:Arylalkylamine N-Acetyltransferase / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008861:Microsomes / Q000201:enzymology; D008875:Middle Aged; D010724:Phosphoadenosine Phosphosulfate / Q000378:metabolism*; D011467:Prostate / Q000201:enzymology*; D011470:Prostatic Hyperplasia / Q000201:enzymology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology
D002273:Carcinogens; D018736:DNA Adducts; D010724:Phosphoadenosine Phosphosulfate; D000105:Acetyl Coenzyme A; D000255:Adenosine Triphosphate; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; C478879:AANAT protein, human; D047068:Arylalkylamine N-Acetyltransferase; D005982:Glutathione Transferase