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Vol. 284, Issue 1, 51-60, 1998
Division of Biochemical Pharmacology, Department of Pharmaceutical
Biosciences, Uppsala Biomedical Center, Uppsala University, Uppsala,
Sweden
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 µM) and furafylline (20 µM),
two inhibitors of CYP1A2, reduced the bisallylic hydroxylation activity
of adult human liver microsomes. Treatment of rats with erythromycin or
dexamethasone induced bisallylic hydroxylation of linoleic acid to
11-HODE in liver microsomes by 2- and 10-fold, respectively. The
biosynthesis of 11-HODE by microsomes of dexamethasone-treated rats was
inhibited by troleandomycin (ED50 = 1 µM) and by
polyclonal antibodies against CYP3A1, suggesting that CYP3A1 could
catalyze bisallylic hydroxylations in the dexamethasone-treated rat. We conclude from steric analysis of 13-HETE and the effects of CYP inhibitors on adult human liver microsomes that CYP1A2 might contribute to its bisallylic hydroxylation activity.
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