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The Effects of Polychlorinated Biphenyls on the Induction of Cytochrome P-450 and Fatty Acid Metabolism.

Huang, Shewen. (1990) The Effects of Polychlorinated Biphenyls on the Induction of Cytochrome P-450 and Fatty Acid Metabolism. Doctoral thesis, University of Surrey (United Kingdom)..

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The effects of seven different xenobiotics on the induction of cytochromes P450 and cytochrome P450-mediated arachidonic acid (AA) metabolism have been examined in the present study. Results from this study have demonstrated that arachidonic acid oxidation catalysed by cytochrome P450 enzymes is highly regioselective. Whereas cytochrome P450 IA, IIB and IVA sub-families catalyse AA oxidation in a regioselective manner, cytochrome P450 IIE1 and IIIA 1(2) isoenzymes do not support any identifiable AA metabolism. Three novel hydroxylated arachidonic acid metabolites (18-, 17- and 16-HETEs) have been successfully generated, purified and structurally characterized from PENCB and 3-MC induced rat liver microsome incubations. Similar metabolite peaks have also been observed from the PENCB-induced guinea pig liver microsome incubations. Species differences in the induction of cytochrome P-450 have been observed between the rat and guinea pig in PENCB treatment, which mainly reside in the induction of cytochrome P-450 IA and IVA sub-families. Whereas PENCB-induced rat hepatic cytochromes P-450 significantly induced the formation of 19-HETE and suppressed 20-HETE formation, PENCB treatment did not affect the 19-HETE formation but induced the 20-HETE formation in the guinea pig, indicative of induction of P-450 IA1 and suppression of P-450 IVA1 in the rat, but no induction of P-450 LA1 and induction of P-450 IVA1 in the guinea pig by PENCB treatment. The present study also demonstrated that the induction of cytochrome P-450 IVA1 by PCB is both congener-specific and species-dependent. Whereas PENCB (MC-type) suppressed the induction of P-450 IVA1 in the rat but induced it in the guinea pig, TCB (PB-type) induced the induction of IVA1 in the rat, but had no effect on the induction of this isoenzyme in the guinea pig at a dose of 300 μmoles/kg. Finally, PENCB exposure resulted in substantial inhibition of fatty acid metabolism in the rat, whereas no such effects of PENCB were observed in the guinea pig. This result casts strong doubt on the possible roles of lipid metabolism disorders in the toxicity of PCBs and related PAH compounds.

Item Type: Thesis (Doctoral)
Divisions : Theses
Authors : Huang, Shewen.
Date : 1990
Additional Information : Thesis (Ph.D.)--University of Surrey (United Kingdom), 1990.
Depositing User : EPrints Services
Date Deposited : 06 May 2020 11:53
Last Modified : 06 May 2020 11:53

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