Cytochrome P450 (CYP) 1A2, sulfotransferase (SULT) 1A1, and N-acetyltransferase (NAT) 2 polymorphisms and susceptibility to urothelial cancer.
OBJECTIVE
Arylamines are suspected to be the primary causative agent of urothelial cancer in tobacco smoke. In the human liver, arylamines are N-hydroxylated by a cytochrome P450 (CYP)1A2-catalyzed reaction, which produces a substrate for O-esterification that can be catalyzed by N-acetyltransferases (NAT) or sulfotransferases (SULT). Recently, several polymorphisms of CYP1A2, SULT1A1, and NAT2 that affect their activities have been reported.


METHODS
In this study, 306 Japanese patients with urothelial transitional cell carcinoma and 306 healthy controls were compared for frequencies of CYP1A2, SULT1A1, and NAT2 genotypes.


RESULTS
The frequencies of NAT2 intermediate or slow acetylator genotype were significantly higher in the urothelial cancer patients than in the healthy control subjects [odds ratio (OR) = 1.49, 95% confidence interval (95% CI) 1.06-2.09, OR = 3.23, 95% CI 1.72-6.08, respectively]. Stratifying by amount of smoking, among subjects who consumed >33.5 pack-years and carried the SULT1A1 *1/*1 or NAT2 slow acetylator genotype, the OR was 1.73 (95% CI 1.01-2.97) whereas it was 7.31 (95% CI 1.90-28.05) in non-smokers who carried the homozygous wild genotype, respectively. The relationships between CYP1A2, SULT1A1, and NAT2 polymorphisms and clinical findings including tumor differentiation, stage, and recurrence rate were analyzed. Only associations between NAT2 genotype and pathological findings were admitted, and the higher OR of NAT2 intermediate and slow acetylator genotype was more likely to present to a low-grade tumor (G1) among heavy-smokers.


CONCLUSIONS
Our results suggest that SULT1A1 *1/*1 and NAT2 slow acetylator genotypes might modulate the effect of carcinogenic arylamines contained in tobacco smoke, and that the modulation of NAT2 intermediate and slow acetylator genotype has a tendency to present a higher risk for highly differentiated tumors among heavy-smokers.
Tsukino
Hiromasa
H
Department of Public Health, Miyazaki Medical College, University of Miyazaki, 5200 Kihara, 889-1692, Japan.
Kuroda
Yoshiki
Y
Nakao
Hiroyuki
H
Imai
Hirohisa
H
Inatomi
Hisato
H
Osada
Yukio
Y
Katoh
Takahiko
T
D000368:Aged; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D015239:Arylsulfotransferase / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D002295:Carcinoma, Transitional Cell / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism*; D014571:Urologic Neoplasms / Q000201:enzymology / Q000235:genetics*; D019459:Urothelium
D019388:Cytochrome P-450 CYP1A2; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human