PMID: 9435160Jan 22, 1998Paper

Cytochromes P450 with bisallylic hydroxylation activity on arachidonic and linoleic acids studied with human recombinant enzymes and with human and rat liver microsomes

The Journal of Pharmacology and Experimental Therapeutics
J BylundE H Oliw

Abstract

Bisallylic carbons of polyunsaturated fatty acids can be hydroxylated in NADPH-dependent reactions in liver microsomes. Human recombinant cytochromes P450 and human and rat liver microsomes were assayed for bisallylic hydroxylation activity. CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP3A4 converted [14C]linoleic acid to 14C-labeled 11-hydroxyoctadecadienoic acid (11-HODE), whereas [14C]arachidonic acid was oxygenated by CYP1A2 and CYP3A4 to 14C-labeled 13-hydroxyeicosatrienoic acid (13-HETE), 10-HETE and 7-HETE as determined by HPLC. Both substrates were also converted to many other metabolites. CYP2C9 appeared to form 12R-HETE and 13-HETE, whereas CYP2C8 formed 13-HETE, 11-HETE and 15-HETE as main monohydroxy metabolites. Fetal human liver microsomes metabolized linoleic acid to 11-HODE as a major hydroxy metabolite, whereas arachidonic acid appeared to be hydroxylated at C13, C20 and, to some extent, at C10, C19 and C7. Fetal liver microsomes mainly formed 13R-HETE, whereas adult human liver microsomes and CYP1A2 mainly formed 13S-HETE. 7,8-Benzoflavone (5 microM) and furafylline (20 microM), two inhibitors of CYP1A2, reduced the bisallylic hydroxylation activity of adult human liver microsomes. Treatment of rats with erythromycin...Continue Reading

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