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Vol. 54, Issue 3, 504-513, September 1998
Laboratories of
Pulmonary Pathobiology (W.Q., J.M., P.S., D.C.Z.),
Experimental Pathology (G.S.T.),
Signal Transduction (C.B.), and
Structural Biology (C.P.), National Institute of Environmental Health
Sciences, Research Triangle Park, North Carolina 27709, and the
Department of Medicine, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599 (F.T.F., R.A.R.)
Alterations in nutritional status affect hepatic cytochrome P450
levels. Since cytochromes P450 participate in the metabolism of
arachidonic acid, we hypothesized that changes in liver P450 arachidonic acid metabolism occur during fasting and refeeding. Male
Fisher 344 rats were either fed, fasted 48 hr (F48), fasted 48 hr and
then refed 6 hr (F48/R6), or fasted 48 hr and then refed 24 hr
(F48/R24). F48 rats had reduced body weight, increased plasma 
-hydroxybutyrate, and reduced plasma insulin compared with the other
groups. Although there was no significant change in total liver P450
content, there was a significant 20%, 48%, and 24% reduction in
total hepatic microsomal arachidonic acid metabolism in F48, F48/R6,
and F48/R24 rats, respectively, compared with fed rats. Epoxygenase
activity decreased by 28%, 51%, and 26% in F48, F48/R6, and F48/R24
rats, respectively. In contrast, 
-1 hydroxylase activity increased
by 126% in F48 rats compared with fed rats. Immunoblotting revealed
that levels of CYP2C11 protein were markedly reduced, whereas levels of
CYP2E1 protein were markedly increased in the F48 and F48/R6 groups. In
contrast, levels of CYP1A1, CYP1A2, CYP2B1, CYP2J3, CYP4A1, and CYP4A3
were unchanged with fasting/refeeding. Northern blots revealed that
levels of CYP2C11 mRNAs were decreased, whereas CYP2E1 mRNAs were
increased in F48 and F48/R6 rats. Recombinant CYP2C11 metabolized
arachidonic acid primarily to epoxides with preference for the
14(S),15(R)-, 11(R),12(S)-, and
8(S),9(R)- epoxyeicosatrienoic acid
enantiomers. We conclude that (1) nutritional status affects hepatic
microsomal arachidonic acid metabolism, (2) reduced epoxygenase
activity in F48 and F48/R6 rats is accompanied by decreased levels of
CYP2C11, (3) increased -1 hydroxylase activity is accompanied by
augmented levels of CYP2E1, and (4) the effects of fasting on CYP2C11
and CYP2E1 expression occur at the pretranslational level.
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