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

Abstract

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.

Role of Human N‐Acetyltransferase 2 Genetic Polymorphism on Aromatic Amine Carcinogen‐Induced DNA Damage and Mutagenicity in a Chinese Hamster Ovary Cell Mutation Assay

“…Hepatic dG-C8-ABP levels were significantly higher in neonatal double NAT knockout mice compared to wild type mice administered ABP (Sugamori et al 2012). Perhaps these findings are influenced by the important role of sulfotransferases in the metabolic activation of ABP in mice (Li et al 2018). Perhaps these findings are influenced by the important role of sulfotransferases in the metabolic activation of ABP in mice (Li et al 2018).…”

The Role of Sulfotransferases in Liver Diseases

“…Besides their classic role in facilitating the detoxification and excretion of their substrates and metabolites, SULT1A1 and SULT1A2 are also known to play a major role in the bioactivation of environmental mutagens and carcinogens, such as hydroxymethyl polycyclic aromatic hydrocarbons, N-hydroxy derivatives of arylamines, allylic alcohols, and heterocyclic amines, leading to mutagenicity and carcinogenesis through the binding of sulfonated metabolites to DNA (Falany, 1997;Weinshilboum et al, 1997;Hempel et al, 2005). Li et al (2018) recently reported that the expression of liver SULT1A1/2 is highly associated with sex-dependent susceptibility of bladder and liver to the major human bladder carcinogen 4-aminobiphenyl (ABP). Both the parent ABP and its sulfonated metabolites are genotoxic (Chou et al, 1995).…”

“…In this study, the authors observed that male bladders were more susceptible than female bladders to ABP. This was explained by the increased bladder exposure to ABP in male mice through androgendependent suppression of ABP sulfation in the liver, leading to increased bladder delivery of carcinogenic ABP (Li et al, 2018). The male preference in the bladder's susceptibility to ABP was attenuated by knocking out the Sult1a1 gene.…”