title: Expression in human prostate of drug- and carcinogen-metabolizing enzymes: association with prostate cancer risk.
abstract: The role of two common polymorphisms of enzymes involved in the metabolism of drugs and carcinogens was studied in relation to prostate cancer. The gene encoding one of these enzymes (NAT2) is located in an area where frequent allelic loss occurs in prostate cancer. Mutations at the genes CYP2D6 and NAT2 were analysed by allele-specific polymerase chain reaction and restriction mapping in DNA from 94 subjects with prostate cancer and 160 male healthy control subjects. Eleven prostate specimens were analysed for genotype and enzymatic activities NAT2, CYP2D6 and CYP3A by using the enzyme-specific substrates sulphamethazine and dextromethorphan. Enzyme activities with substrate specificities corresponding to NAT2, CYP2D6 and CYP3A are present in human prostate tissue, with mean +/-s.d. activities of 4.8+/-4.4 pmol min(-1) mg(-1) protein, 156+/-91 and 112+/-72 nmol min(-1) mg(-1) protein respectively. The Km values for the prostate CYP2D6 and CYP3A enzyme activities corresponded to that of liver CYP2D6 and CYP3A activities, and the CYP2D6 enzyme activity is related to the CYP2D6 genotype. The N-acetyltransferase, in contrast, had a higher Km than NAT2 and was independent of the NAT2 genotype. The CYP2D6 and CYP3A enzymes, and an N-acetyltransferase activity that is independent of the regulation of the NAT2 gene, are expressed in human prostate tissue. The presence of carcinogen-metabolizing enzymes in human prostate with a high interindividual variability may be involved in the regulation of local levels of carcinogens and mutagens and may underlie interindividual differences in cancer susceptibility.
authors.affiliation: Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Agúndez
authors.forename: C
authors.initials: C
authors.lastname: Martínez
authors.forename: M
authors.initials: M
authors.lastname: Olivera
authors.forename: L
authors.initials: L
authors.lastname: Gallardo
authors.forename: J M
authors.initials: JM
authors.lastname: Ladero
authors.forename: C
authors.initials: C
authors.lastname: Rosado
authors.forename: J
authors.initials: J
authors.lastname: Prados
authors.forename: J
authors.initials: J
authors.lastname: Rodriguez-Molina
authors.forename: L
authors.initials: L
authors.lastname: Resel
authors.forename: J
authors.initials: J
authors.lastname: Benítez
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors
chemical_list: D019389:Cytochrome P-450 CYP2D6; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human