Isoform‐selective changes in arachidonic acid (AA) metabolizing cytochrome P450 (P450) enzymes in warm hepatic ischemia (IR) reperfusion injury

Abstract

The objective of this study was to investigate the effects of warm hepatic IR injury on the major P450 enzymes responsible for epoxygenation (CYP2J2 and CYP2C23) and ω/ω‐1 hydroxylation (CYP4A) of AA in rats. Four groups of rats (n = 5–6/group) were subjected to 60 min of in vivo partial (70%) hepatic ischemia or sham operation, followed by 3 or 24 hr of reperfusion. Liver microsomes and plasma samples, collected at the end of the reperfusion period, were used for quantitation of alanine aminotransferase (ALT) concentrations and the protein levels of CYP4A, CYP2C23, and CYP2J2 (Western blot), respectively. Compared with sham‐operated animals, IR caused 10‐ and 3.3‐fold increases in the ALT concentrations after 3 and 24 hr of reperfusion, respectively (P<0.0001). In the 3‐hr reperfusion group, IR caused no changes in the expression of CYP4A and CYP2C23, whereas it down regulated CYP2J2 levels by 19.7% (P<0.01). In the 24‐hr reperfusion group, IR caused no changes in the expression of CYP2J2, whereas it upregulated CYP4A by 46.5% (P<0.05) and CYP2C23 by 56.1% (P<0.05). These results suggest that warm hepatic IR causes isoform‐selective changes in the AA‐metabolizing enzymes, potentially altering hepatic disposition of P450‐mediated metabolites of AA. Financial Support: Texas Higher Education Coordinating Board and Texas Tech School of Pharmacy Vascular Drug Research Center.