Date of Award

8-2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Environmental Toxicology

Advisor

Baldwin, William S

Committee Member

Bain , Lisa

Committee Member

Rice , Charles

Committee Member

Yu , Xianzhong

Abstract

The Cyp2b subfamily contains five members (Cyp2b9, Cyp2b10, Cyp2b13, Cyp2b19, and Cyp2b23) of which three (Cyp2b9, Cyp2b10, Cyp2b13) are hepatic enzymes involved in xenobiotic detoxification. In this study, we made a Cyp2b-knockdown mouse using lentiviral-promoted shRNA homologous to all five Cyp2b subfamily members in FVB/NJ mouse to characterize Cyp2b's role in xenobiotic detoxification. We assessed the in vivo function of Cyp2bs in the toxicity from pesticides (i.e. parathion) and drugs (i.e. zoxazolamine). We demonstrated that Cyp2b isoforms play a key role in parathion and Zoxazolamine metabolism and toxicity. In addition, we in partially phenotyped and characterized Cyp2b-KD model and assessed changes associated with the lack of Cyp2bs. We focused on role that Cyp2bs play in lipid metabolism. Changes in Cyp2b expression led to perturbation in lipid metabolism in Cyp2b-KD mice. Both young and old Cyp2b-KD male and female mice showed significant changes in some organ weights, especially an increase in abdominal, inguinal, and renal adipose. Interestingly, associated with changes in fat to body ratios was changes in non-fasting triglycerides levels. Our data suggest that Cyp2b is more than a detoxification enzyme, but is also involved in the metabolism of unsaturated fatty acids as Cyp2b-KD mice have increased fat deposition and show increased serum and liver lipid levels.

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