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...
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| Format: | Article |
| Language: | English |
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Wiley
2018-11-01
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| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.1779 |
| _version_ | 1827814304700694528 |
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| author | Yun Li Zhidan Chen Joseph D. Paonessa Walter Meinl Arup Bhattacharya Hansruedi Glatt Paul Vouros Yuesheng Zhang |
| author_facet | Yun Li Zhidan Chen Joseph D. Paonessa Walter Meinl Arup Bhattacharya Hansruedi Glatt Paul Vouros Yuesheng Zhang |
| author_sort | Yun Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T23:44:37Z |
| format | Article |
| id | doaj.art-0bd0fa53678549dd93c5657143a196ac |
| institution | Directory Open Access Journal |
| issn | 2045-7634 |
| language | English |
| last_indexed | 2024-03-11T23:44:37Z |
| publishDate | 2018-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj.art-0bd0fa53678549dd93c5657143a196ac2023-09-19T11:30:57ZengWileyCancer Medicine2045-76342018-11-017115604561010.1002/cam4.1779Strong impact of sulfotransferases on DNA adduct formation by 4‐aminobiphenyl in bladder and liver in miceYun Li0Zhidan Chen1Joseph D. Paonessa2Walter Meinl3Arup Bhattacharya4Hansruedi Glatt5Paul Vouros6Yuesheng Zhang7Department of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center Buffalo New YorkBarnett Institute and Department of Chemistry and Chemical Biology Northeastern University Boston MassachusettsDepartment of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center Buffalo New YorkDepartment of Molecular Toxicology German Institute of Human Nutrition Potsdam‐Rehbruecke (DIfE) Nuthetal GermanyDepartment of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center Buffalo New YorkDepartment of Food Safety German Federal Institute for Risk Assessment (BfR) Berlin GermanyBarnett Institute and Department of Chemistry and Chemical Biology Northeastern University Boston MassachusettsDepartment of Pharmacology and Therapeutics Roswell Park Comprehensive Cancer Center Buffalo New YorkAbstract 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.https://doi.org/10.1002/cam4.17794‐Aminobiphenylbladder cancergender‐related risk of bladder cancersulfotransferasetobacco carcinogen |
| spellingShingle | Yun Li Zhidan Chen Joseph D. Paonessa Walter Meinl Arup Bhattacharya Hansruedi Glatt Paul Vouros Yuesheng Zhang Strong impact of sulfotransferases on DNA adduct formation by 4‐aminobiphenyl in bladder and liver in mice Cancer Medicine 4‐Aminobiphenyl bladder cancer gender‐related risk of bladder cancer sulfotransferase tobacco carcinogen |
| title | Strong impact of sulfotransferases on DNA adduct formation by 4‐aminobiphenyl in bladder and liver in mice |
| title_full | Strong impact of sulfotransferases on DNA adduct formation by 4‐aminobiphenyl in bladder and liver in mice |
| title_fullStr | Strong impact of sulfotransferases on DNA adduct formation by 4‐aminobiphenyl in bladder and liver in mice |
| title_full_unstemmed | Strong impact of sulfotransferases on DNA adduct formation by 4‐aminobiphenyl in bladder and liver in mice |
| title_short | Strong impact of sulfotransferases on DNA adduct formation by 4‐aminobiphenyl in bladder and liver in mice |
| title_sort | strong impact of sulfotransferases on dna adduct formation by 4 aminobiphenyl in bladder and liver in mice |
| topic | 4‐Aminobiphenyl bladder cancer gender‐related risk of bladder cancer sulfotransferase tobacco carcinogen |
| url | https://doi.org/10.1002/cam4.1779 |
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