The inverse relationship between bladder and liver in 4-aminobiphenyl-induced DNA damage
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Arup Bhattacharya1,*, Joshua J. Klaene2,*, Yun Li1,3,*, Joseph D. Paonessa1,*, Aimee B. Stablewski4, Paul Vouros2, Yuesheng Zhang1
1Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, NY, USA
2Barnett Institute and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA
3Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA
4Department of Molecular & Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
*These authors have contributed equally to this work
Yuesheng Zhang, e-mail: email@example.com
Keywords: Bladder cancer, 4-aminobiphenyl, DNA damage, UDP-glucuronosyltransferase
Received: August 29, 2014 Accepted: November 08, 2014 Published: December 17, 2014
Bladder cancer risk is significantly higher in men than in women. 4-Aminobiphenyl (ABP) is a major human bladder carcinogen from tobacco smoke and other sources. In mice, male bladder is more susceptible to ABP-induced carcinogenesis than female bladder, but ABP is more carcinogenic in the livers of female mice than of male mice. Here, we show that castration causes male mice to acquire female phenotype regarding susceptibility of bladder and liver to ABP. However, spaying has little impact on organ susceptibility to ABP. Liver UDP-glucuronosyltransferases (UGTs) are believed to protect liver against but sensitize bladder to ABP, as glucuronidation of ABP and its metabolites generally reduces their toxicity and promotes their elimination via urine, but the metabolites are labile in urine, delivering carcinogenic species to the bladder. Indeed, liver expression of ABP-metabolizing human UGT1A3 transgene in mice increases bladder susceptibility to ABP. However, ABP-specific liver UGT activity is significantly higher in wild-type female mice than in their male counterparts, and castration also significantly increases ABP-specific UGT activity in the liver. Taken together, our data suggest that androgen increases bladder susceptibility to ABP via liver, likely by modulating an ABP-metabolizing liver enzyme, but exclude UGT as an important mediator.
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