Inhibitory effect of nitric oxide on the metabolism of halogenated volatile anesthetics by cytochrome P-450

Abstract

Purpose. This study was undertaken to examine the effect of nitric oxide (NO) on the metabolism of halogenated volatile anesthetics (HVA) by cytochrome P-450 (CYP) under both aerobic and anaerobic conditions using rat hepatic microsomes.

Methods. A microsomal fraction was prepared by centrifugation from normal and phenobarbital-treated male SD rats. The anaerobic metabolism of HVA by CYP was followed by measuring the formation of a halothane CYP complex spectrophotometrically. Aerobic CYP activity was determined using either the defluorination of sevoflurane or the demethylation of aminopyrine.

Results. The formation of the halothane-CYP complex was dose-dependently inhibited by NO. NO also decreased CYP defluorination of halothane in a dose-dependent manner. In phenobarbital-induced microsomes, the inhibition rates of both complex formation and the defluorination of halothane were the same as those seen in normal microsomes. Although the defluorination of sevoflurane and the demethylation of aminopyrine were inhibited by NO aerobically, the inhibition was much less than that of the metabolism of halothane under anaerobic conditions.

Conclusion. These results suggest that NO binds the heme of CYP and inhibits the metabolism of HVA, with the effect lasting for a prolonged period of time. Furthermore, the balance between NO and O₂ is important for NO to inhibit CYP.