Reductive metabolism of halothane by human and rabbit cytochrome P- 450. Binding of 1-chloro-2,2,2-trichloroethyl radical to phospholipids.

Details

• Personal Author:
  Bosterling B ; Trevor AJ ; Trudell JR
• Description:
  A comparison was made of the most well studied cytochrome-P-450, phenobarbital induced rabbit cytochrome-P-450LM-2, with the major component of noninduced human liver-cytochrome-P-450 isolated, cytochrome-P-450HA-2. Cytochrome-b5 was also included in the reconstituted systems to better duplicate the conditions that exist in the endoplasmic reticulum of liver cells. The human and rabbit reconstituted cytochrome-P-450 systems were incubated under an argon atmosphere in the presence of NADPH with halothane (151677) for one hour and studied in parallel with an intact microsomal suspension of comparable cytochrome-P-450 content, in order to measure whether the rate of metabolite binding to phospholipids previously noted in microsomes was duplicated in the reconstituted systems. The findings indicated that cytochrome-P-450 was able to form a free radical from a halocarbon by one electron reduction and to release the free radical into the matrix of surrounding phospholipids. NADPH-cytochrome-P-450 reductase did not carry out this reduction in the absence of cytochrome-P-450. It was likely that this pathway of reductive metabolism was a general one for halocarbons in incubations in-vitro of reconstituted cytochrome-P-450 under anaerobic conditions and in exposures in-vivo under conditions that cause very low hepatic oxygen concentrations. Most likely the free radical formed following the first step of 1-chloro-2,2,2- trifluroethyl radical addition to a double bond was the intermediate for the subsequent steps of conjugation of double bonds and lipoperoxidation that may be the initiating steps of hepatic necrosis following exposure to halothane. [Description provided by NIOSH]
• Subjects:
  Anesthesia Digestive System Digestive System Diseases Energy Metabolism Halothane Liver Occupational Health Safety
• Keywords:
  NIOSH-Publication; NIOSH-Grant; Grants-other; Liver-enzymes; Metabolic-study; Anesthetics; Liver-damage; Halogenated-hydrocarbons
• ISSN:
  0026-895X
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  California ; OSHA Region 9
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  21
• Issue:
  3
• NIOSHTIC Number:
  nn:00190477
• Citation:
  Mol Pharmacol 1982 May; 21(3):710-717
• Contact Point Address:
  Anesthesia Stanford University Department of Anesthesia Stanford, Calif 94305
• CAS Registry Number:
  (±)-Halothane (CAS RN 151-67-7)
• Federal Fiscal Year:
  1982
• NORA Priority Area:
  Other Occupational Concerns ; Grants Other
• Performing Organization:
  Stanford University, Stanford, California
• Peer Reviewed:
  True
• Start Date:
  19800901
• Source Full Name:
  Molecular Pharmacology
• End Date:
  19901130
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:7dc847c09aedf140bc731323e8446b4703641ae07d6ad9e7b7238120dab30b8f7dcaa9b938d34d035f87873a0fe7fec262d5d13dcaf290925445e82b6de3b57d
• Download URL:
  https://stacks.cdc.gov/view/cdc/247706/cdc_247706_DS1.pdf
• File Type:
  [PDF - 168.02 KB ]