Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.592621
Title: Species differences in the induction of cytochrome P4503A
Author: Jackson, F. C.
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1998
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Abstract:
Species differences in the induction mechanisms of CYP3A isoenzymes were investigated in this project using several structurally different drugs in rat, dog or human in vitro and in vivo models. Induction of CYP3A was assessed by observing the levels of CYP3A activity, CYP3A immunoreactive protein and CYP3A mRNA following drug treatment. Dexamethasone was a potent inducer of CYP3A activity, protein and mRNA in the female rat in vivo and in vitro. The induction of CYP3A by dexamethasone was inhibited by the presence of 5% FCS in rat hepatocytes and a residual inhibitory effect was observed when 5% FCS was used for cell attachment only. The inhibition of CYP3A induction by FCS was not observed in dog or human hepatocytes. Dexamethasone did not induce CYP3A activity in the male or female dog in vivo. Rifampicin was a potent inducer of CYP3A in the dog in vitro, which correlates with the effect of rifampicin on CYP3A in dog in vivo. The ACAT inhibitor, SK&F 98016, induced CYP3A activity and protein in the rat in vivo and in vitro whilst mRNA levels were increased in vivo but not in vitro. The HMGCo-A reductase inhibitors, lovastatin and simvastatin induced CYP3A protein and activity in the rat in vivo but had no effect on CYP3A mRNA levels. Lovastatin and simvastatin did not induce CYP3A in the rat in vitro. Addition of the cholesterol biosynthesis pathway intermediates mevalonate and 25-hydroxycholestrol enhanced the induction of CYP3A by SK&F 98016 in the rat in vitro, suggesting that oxysterols may be involved in the induction of CYP3A by SK&F 98016. Different induction mechanisms are involved between dexamethasone-mediated CYP3A induction and the induction of CYP3a by SK&F 98016 and the statins. Dexamethasone induces CYP3A through an interaction with a 'non-classical' glucocorticoid receptor, whilst SK&F 98016 and the statins inhibit ACAT and HMGCo-A reductase in the cholesterol biosynthesis pathway, leading to an alteration in the level of regulatory oxysterols. This suggests a link between the regulation of the cholesterol biosynthesis pathway and the induction of CYP3A by SK&F 98016 and the statins.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.592621  DOI: Not available
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