Strong impact of sulfotransferases on DNA adduct formation by 4‐aminobiphenyl in bladder and liver in mice

Bladder cancer risk is 3‐4 times higher in men than women, but the reason is poorly understood. In mice, male bladder is also more susceptible than female bladder to 4‐aminobiphenyl (ABP), a major human bladder carcinogen; however, female liver is more susceptible than male liver to ABP. We investigated the role of sulfotransferase (Sult) in gender‐related bladder and liver susceptibility to ABP. Sulfation reactions of aromatic amine bladder carcinogens catalyzed by Sult may generate highly unstable and toxic metabolites. Therefore, liver Sult may decrease bladder exposure to carcinogens by promoting their toxic reactions in the liver. Notably, the expression of several liver Sults is suppressed by androgen in male mice. Here, we show that two Sults are critical for gender‐related bladder susceptibility to ABP in mice. We measured tissue level of N ‐(deoxyguanosin‐8‐yl)‐4‐aminobiphenyl (dG‐C8‐ABP), a principal ABP‐DNA adduct, as readout of tissue susceptibility to ABP. We identified Sutl1a1 and to a lesser extent Sult1d1 as Sults that promote dG‐C8‐ABP formation in hepatic cells. In mice, gender gap in bladder susceptibility to ABP was narrowed by knocking out Sult1a1 and was almost totally eliminated by knocking out both Sutl1a1 and Sult1d1. This was accompanied by dramatic decrease in ABP genotoxicity in the liver (>97%). These results show the strong impact of the Sults on bladder and liver susceptibility to a human carcinogen. Because liver expression of both Sult1a1 and Sutl1d1 is suppressed by androgen in male mice, our results suggest that androgen renders bladder more exposed to ABP in male mice by suppressing Sult‐mediated ABP metabolism in liver, which increases bladder delivery of carcinogenic metabolites.