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N-Glucuronidation of 4-Aminobiphenyl and the Risk of Urinary Bladder Cancer: Gender Differences

Al-Zoughool, Mustafa Hussein
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1115852691

Abstract Details

2005, PhD, University of Cincinnati, Medicine : Toxicology (Environmental Health).
The current study is aimed at investigating the role of N-glucuronidation in the organotropic differences between males and females using the bladder carcinogen, 4-aminobiphenyl (4-ABP). In order to assess the levels of male and female N-glucuronidation of 4-ABP we have developed a new HPLC method and optimized the N-glucuronidation assay. The method’s maximum accuracy and precision were -12 % and 9.8 %, respectively. It has comparable or better sensitivity to the old methods which use the radioactive [C14]-UDPGA. Optimal incubation time of the UGT reaction was in the range of 20-90 minutes and the optimal amount of microsomal proteins was 0.1-0.5 mg/reaction. Alamethicin was the best reagent to activate microsomes at a concentration of 50 µg alamethicin/mg protein. In the in vivo study, we treated male and female mice with 4-ABP after modulating their 4-ABP N-glucuronidation using the plant steroid, hecogenin and then determined the distribution of 4-ABP adducts in liver and bladder. In animals treated with 4-ABP only, males had statistically significant higher levels of DNA adducts in the bladder (p-value 0.0004) while females had statistically significant higher levels in the liver (p-value <0.0001). Hecogenin co-treatment increased the levels of DNA adducts in the liver in both males and females but this increase was statistically significant only in males (p-value 0.0024). There was a slight decrease in the levels of DNA adducts in the bladder of both males and females with hecogenin co-treatment, but this decrease was statistically insignificant. Using two-way ANOVA, we found that gender and hecogenin treatment both had a statistically significant effect on liver DNA adduct levels, whereas only gender had statistically significant effect on bladder adduct levels where males have about 2.2-fold higher DNA adducts than females. The current data suggests that N-glucuronidation of 4-ABP may actually have an impact on the distribution of DNA damage. The fact that there was only a slight decrease in bladder adduct levels compared to the significant increase in the liver indicates that besides N-glucuronidation, conjugation and metabolic activation by other enzymes may also contribute to the transport of the proximate metabolites of 4-ABP to the bladder.
Dr. Glenn Talaska (Advisor)
105 p.
Health Sciences, Toxicology
4-Aminobiphenyl; Bladder cancer; Aromatic amines; N-glucuronidation; DNA-adducts

Recommended Citations

Citations

  • Al-Zoughool, M. H. (2005). N-Glucuronidation of 4-Aminobiphenyl and the Risk of Urinary Bladder Cancer: Gender Differences [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1115852691

    APA Style (7th edition)

  • Al-Zoughool, Mustafa. N-Glucuronidation of 4-Aminobiphenyl and the Risk of Urinary Bladder Cancer: Gender Differences. 2005. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1115852691.

    MLA Style (8th edition)

  • Al-Zoughool, Mustafa. "N-Glucuronidation of 4-Aminobiphenyl and the Risk of Urinary Bladder Cancer: Gender Differences." Doctoral dissertation, University of Cincinnati, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1115852691

    Chicago Manual of Style (17th edition)

ucin1115852691
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© 2005, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.