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Human liver microsomal enflurane defluorination catalyzed by cytochrome P-450 2E1.

Publication ,  Journal Article
Thummel, KE; Kharasch, ED; Podoll, T; Kunze, K
Published in: Drug Metab Dispos
1993

The volatile anesthetic agent enflurane undergoes oxidative metabolism in human liver, yielding both inorganic and organic fluoride metabolites. Numerous studies conducted in animals indicate that the enzyme cytochrome P-450 2E1 is a major catalyst for the defluorination reaction. However, the P-450 enzyme catalyzing enflurane metabolism in humans has not been identified. Therefore, experiments were conducted to determine whether hepatic P-450 2E1 is a catalyst for the reaction in humans, and whether other constitutive or inducible isoforms might also be involved. Purified human liver P-450 2E1, reconstituted with cytochrome b5 and P-450 reductase, catalyzed enflurane defluorination at a rate of 9.3 nmol F-/nmol P-450/30 min, in contrast to a mean liver microsomal rate of 2.0 nmol F-/nmol P-450/30 min. The microsomal rate of defluorination for individual human livers correlated significantly with the microsomal content of P-450 2E1 protein (r = 0.92), the rate of p-nitrophenol hydroxylation (r = 0.86), and the rate of chlorzoxazone 6-hydroxylation (r = 0.90). In addition, specific anti-P-450 2E1 IgG, at a concentration of 10 mg IgG/nmol P-450 inhibited the microsomal reaction by 80%. Finally, a series of P-450 isoform-specific chemical inhibitors of oxidative metabolism--furafylline (1A2), sulfaphenazole (2C9/10), quinidine (2D6), troleandomycin (3A3/4), and diethyldithiocarbamate (2E1)--were screened for their ability to block human microsomal enflurane defluorination. Only diethyldithiocarbamate, a mechanism-based inhibitor of P-450 2E1, inhibited the reaction; this occurred to a degree comparable to the effect of anti-P-450 2E1 antibody.(ABSTRACT TRUNCATED AT 250 WORDS)

Duke Scholars

Published In

Drug Metab Dispos

ISSN

0090-9556

Publication Date

1993

Volume

21

Issue

2

Start / End Page

350 / 357

Location

United States

Related Subject Headings

  • Rats
  • Pharmacology & Pharmacy
  • Microsomes, Liver
  • Male
  • In Vitro Techniques
  • Immunoglobulin G
  • Humans
  • Enflurane
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 Enzyme Inhibitors
 

Citation

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Thummel, K. E., Kharasch, E. D., Podoll, T., & Kunze, K. (1993). Human liver microsomal enflurane defluorination catalyzed by cytochrome P-450 2E1. Drug Metab Dispos, 21(2), 350–357.
Thummel, K. E., E. D. Kharasch, T. Podoll, and K. Kunze. “Human liver microsomal enflurane defluorination catalyzed by cytochrome P-450 2E1.Drug Metab Dispos 21, no. 2 (1993): 350–57.
Thummel KE, Kharasch ED, Podoll T, Kunze K. Human liver microsomal enflurane defluorination catalyzed by cytochrome P-450 2E1. Drug Metab Dispos. 1993;21(2):350–7.
Thummel, K. E., et al. “Human liver microsomal enflurane defluorination catalyzed by cytochrome P-450 2E1.Drug Metab Dispos, vol. 21, no. 2, 1993, pp. 350–57.
Thummel KE, Kharasch ED, Podoll T, Kunze K. Human liver microsomal enflurane defluorination catalyzed by cytochrome P-450 2E1. Drug Metab Dispos. 1993;21(2):350–357.

Published In

Drug Metab Dispos

ISSN

0090-9556

Publication Date

1993

Volume

21

Issue

2

Start / End Page

350 / 357

Location

United States

Related Subject Headings

  • Rats
  • Pharmacology & Pharmacy
  • Microsomes, Liver
  • Male
  • In Vitro Techniques
  • Immunoglobulin G
  • Humans
  • Enflurane
  • Cytochrome P-450 Enzyme System
  • Cytochrome P-450 Enzyme Inhibitors