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.

Miwako Saito, Toshiyuki Okutomi, Makiko Shimizu, Yoshiaki Matsumoto, Hiroshi Yamazaki, Sumio Hoka

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)201-207
Number of pages7
JournalDrug metabolism and pharmacokinetics
Volume21
Issue number3
DOIs
Publication statusPublished - Jun 2006

Fingerprint

Cytochrome P-450 CYP3A
Magnesium Sulfate
Bupivacaine
Liver Microsomes
Testosterone
Protein Isoforms
Cytochromes b5
NADPH-Ferrihemoprotein Reductase
Hydroxylation
Intravenous Administration
Biotransformation
Cytochrome P-450 Enzyme System
Seizures
Complementary DNA
Electrons

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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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. / Saito, Miwako; Okutomi, Toshiyuki; Shimizu, Makiko; Matsumoto, Yoshiaki; Yamazaki, Hiroshi; Hoka, Sumio.

In: Drug metabolism and pharmacokinetics, Vol. 21, No. 3, 06.2006, p. 201-207.

Research output: Contribution to journalArticle

Saito, Miwako ; Okutomi, Toshiyuki ; Shimizu, Makiko ; Matsumoto, Yoshiaki ; Yamazaki, Hiroshi ; Hoka, Sumio. / 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. In: Drug metabolism and pharmacokinetics. 2006 ; Vol. 21, No. 3. pp. 201-207.
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abstract = "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.",
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