Reductive metabolism of halothane by human and rabbit cytochrome P- 450. Binding of 1-chloro-2,2,2-trichloroethyl radical to phospholipids.
Trudell-JR; Bosterling-B; Trevor-AJ
Mol Pharmacol 1982 May; 21(3):710-717
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.
NIOSH-Publication; NIOSH-Grant; Grants-other; Liver-enzymes; Metabolic-study; Anesthetics; Liver-damage; Halogenated-hydrocarbons
Anesthesia Stanford University Department of Anesthesia Stanford, Calif 94305
Other Occupational Concerns; Grants-other
Stanford University, Stanford, California