Activities of rat cytochrome P450 3A and 2C isoforms are increased in vivo by magnesium sulfate as evidenced by enhanced oxidation of bupivacaine and testosterone in liver microsomes.

We previously reported that magnesium sulfate (MgSO(4)) increases the threshold dose of bupivacaine in inducing seizure in rats. Cytochrome P450 (P450) isoforms involved in the biotransformation of bupivacaine to three oxidative metabolites and the effects of MgSO(4) in vivo on the P450 activities in rats were investigated. Of six cDNA-expressed rat P450 isoforms tested, CYP3A2 and CYP2C11 had high rates for N-debutlylation and 3'-hydroxylation of bupivacaine, respectively. The liver microsomes prepared from male rats pretreated with intravenous administration of MgSO(4) (a bolus dose of 25 mg/kg, followed by infusion of 2.0 mg/kg/min for 6 h) showed increased V(max) values for N-debutylation and 3'-hydroxylaiton of bupivacaine compared to the liver microsomes from control rats. Administration of MgSO(4) also increased the activities of testosterone 6beta- and 16alpha-hydroxylation. Although the level of expression of CYP3A and CYP2C isoforms in the liver microsomes were unchanged, NADPH-P450 reductase and cytochrome b(5) were found to be induced by intravenous administration of MgSO(4). These results suggest that CYP3A and CYP2C isoforms are activated by MgSO(4) in vivo as a consequence of enhanced microsomal electron transfer due to induction of NADPH-P450 reductase and cytochrome b(5), leading to the increased metabolism and clearance of bupivacaine.