Variation in enzymes of arylamine procarcinogen biotransformation among bladder cancer patients and control subjects.
Arylamines such as 2-naphthylamine and 4-aminobiphenyl are suspected human bladder procarcinogens that require bioactivation to DNA-reactive species to exert their carcinogenic potential. The goals of the present study were (i) to assay for the presence of the arylamine acetyltransferases NAT1 and NAT2, and of the cytochrome P450 isoform CYP1A2, in human bladder epithelium; and (ii) to determine whether the activities of these arylamine biotransforming enzymes differ between bladder cancer patients and control subjects. We measured in-vitro enzyme activities in biopsies of normal, undiseased bladder epithelium obtained from 103 bladder cancer patients. NAT1 activity was detectable in all samples, with mean levels higher than those found in human liver. Kinetic evidence also suggested low levels of NAT2 expression in this tissue, but there was no detectable CYP1A2 by either enzymatic or immunochemical measurements. We also compared several probe drug indices of in-vivo NAT1, NAT2 and CYP1A2 activity between 53 bladder cancer patients and 96 cancer-free control subjects who were carefully matched for age, gender and smoking status. NAT1 and NAT2 genotypes were also determined. No significant differences were found between bladder cancer patients and control subjects for a number of individual phenotypic or genotypic predictors of enzyme function. Our results suggest that although expression of particular arylamine biotransforming enzymes within the bladder tissue could play a significant role in locally bioactivating arylamine procarcinogens in theory, interindividual variations in CYP1A2, NAT1 and NAT2 activities do not significantly differ between bladder cancer patients and control subjects when potential arylamine exposures are controlled for
Vaziri
S A
SA
Genetics and Genomnic Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Canada. vaziris@ccf.org
Hughes
N C
NC
Sampson
H
H
Darlington
G
G
Jewett
M A
MA
Grant
D M
DM
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D002295:Carcinoma, Transitional Cell / Q000201:enzymology* / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D005838:Genotype; D006801:Humans; D007527:Isoenzymes; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011237:Predictive Value of Tests; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000378:metabolism; D019459:Urothelium / Q000201:enzymology
D002273:Carcinogens; D007527:Isoenzymes; D019388:Cytochrome P-450 CYP1A2; D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human