Received for publication January 27, 2006.
Revised April 29, 2006.
Accepted for publication May 12, 2006.

Induction of CYP1A and CYP2 mediated archidonic acid epoxidation and suppression of 20-HETE by imidazole derivatives including the aromatase inhibitor vorozole

Abstract

Cytochrome P450 enzymes metabolize the membrane lipid arachidonic acid to stable biologically active epoxides (EETs) and 20-HETE. These products have cardiovascular activity, primarily acting as vasodilators and vasoconstrictors, respectively. EET formation can be increased by the prototype CYP1A or CYP2 inducers, TCDD or phenobarbital, respectively. We report here that imidazole derivative drugs: the antihelminthics, albendazole and thiabendazole, the proton pump inhibitor, omeprazole, the thromboxane synthase inhibitor, benzylimidazole, and the aromatase (CYP19) inhibitor vorozole (R76713, racemate and R83842, (+) enantiomer) increased hepatic microsomal EET formation in a chick embryo model. Albendazole increased EETs by transcriptional induction of CYP1A5 and the others by combined induction of CYP1A5 and CYP2H, the avian orthologs of mammalian CYP1A2 and CYP2B, respectively. All inducers increased formation of the four EET regioisomers , but TCDD and albendazole had preference for 5,6-EET and PB and omeprazole for 14,15-EET. Vorozole, benzylimidazole and TCDD also suppressed 20-HETE formation. Vorozole was a remarkably effective and potent inducer of multiple hepatic CYPs at a dose range which overlapped its inhibition of ovarian aromatase. Increased CYP1A activity in mouse Hepa 1-6 and human HepG2 cells by vorozole and other imidazole derivatives demonstrated applicability of the findings to mammalian cells. The findings suggest that changes in CYP-dependent arachidonic acid metabolism may be a new source of side for drugs that induce CYP1A or CYP2. They demonstrate further that in vivo induction of multiple hepatic CYPs produces additive increases in AA epoxygenase activity and can occur concurrently with inhibition of ovarian aromatase activity.

Key words: arachidonic acid metabolism, CYP induction, CYP1A, CYP2B, eicosanoids, liver microsomes, chick embryo cytochrome P450, aromatase inhibitors, imidazole drugs

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