Association of genotypes of carcinogen-activating enzymes, phenol sulfotransferase SULT1A1 (ST1A3) and arylamine N-acetyltransferase NAT2, with urothelial cancer in a Japanese population.
Carcinogenic aromatic amines such as 4-aminobiphenyl, which is contained in tobacco smoke, are one of the causal factors of urothelial epithelial cancers. 4-Aminobiphenyl has been shown to be bioactivated through N-hydroxylation by hepatic cytochrome (CYP) 1A2 and subsequently through O-sulfation and O-acetylation by phenol sulfating sulfotransferase, ST1A3 (SULT1A1), and arylamine N-acetyltransferase, NAT2, respectively. In a case-control study for urothelial epithelial cancers, low activity alleles of NAT2 are overall high-risk alleles (OR 2.11; 95% CI 1.08-4.26). Wild-type ST1A3*1 ((213)Arg) alleles were slightly overrepresented in nonsmoking urothelial cancer patients (82.6% vs. 69.7%) and in smoking cancer patients (76.7% and 74.3%) compared to a variant ST1A3*2 ((213)His) allele. In combination of ST1A3 and NAT2 genotypes for analyses of urothelial cancer risk, the highest OR of 2.45 (95% CI 1.04-5.98) was obtained with ST1A3*1 and NAT2 slow genotype among the 4 combinations. Recombinant ST1A3*1 enzyme showed a tendency of catalyzing higher in vitro 3'-phosphoadenosine 5'-phosphosulfate-dependent DNA adduct formation than ST1A3*2 (2.84 +/- 0.49 and 2.22 +/- 0.11 adducts/10(8) nucleotides). Combined analyses of different alleles of carcinogenic aromatic amine-activating phase II enzymes were applied to urothelial cancer risk for the first time and showed the highest risk combination of ST1A3 and NAT2 alleles.
Ozawa
Shogo
S
Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan. sozawa@nihs.go.jp
Katoh
Takahiko
T
Inatomi
Hisato
H
Imai
Hirohisa
H
Kuroda
Yoshiki
Y
Ichiba
Masayoshi
M
Ohno
Yasuo
Y
D000368:Aged; D000611:Aminobiphenyl Compounds / Q000378:metabolism; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D015239:Arylsulfotransferase; D016022:Case-Control Studies; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D018736:DNA Adducts; D005260:Female; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007564:Japan / Q000453:epidemiology; D008297:Male; D010724:Phosphoadenosine Phosphosulfate / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D051381:Rats; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D015238:Sulfotransferases / Q000235:genetics* / Q000378:metabolism; D014571:Urologic Neoplasms / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics
D000611:Aminobiphenyl Compounds; D018736:DNA Adducts; D010724:Phosphoadenosine Phosphosulfate; D019388:Cytochrome P-450 CYP1A2; D001191:Arylamine N-Acetyltransferase; D015238:Sulfotransferases; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human