Halothane: inhibition and activation of rat hepatic glutathione S-transferases.
Multiple halothane anesthesias (1.25 MAC for 1 hr on 3 alternate days) of male Long-Evans rats initially decreased by up to 30% and subsequently increased to up to 185% liver cytosolic glutathione S-transferase activity toward 1-chloro-2,4-dinitrobenzene, 3,4-dichloro-1-nitrobenzene and trans-4-phenyl-3-buten-2-one and glutathione peroxidase activity. Halothane rapidly and reversibly activated hepatic cytosolic glutathione S-transferases and purified isoenzyme 1-2 but not isoenzymes 1-1 and 3-3. At high concentrations of halothane (ca. 22 mM), maximal activation was ca. 25%. Halothane, enflurane, isoflurane and methoxyflurane, but not the halothane metabolite 1-chloro-2,2-difluoroethylene, inhibited a mixture of liver cytosolic glutathione S-transferases with time (ca. 30% inhibition/15 min). The inhibition exhibited pseudo-first order kinetics (kobs = 0.13 min-1) and an I50 for halothane of greater than or equal to 15 mM. Halothane inhibited glutathione S-transferases 3-3, 3-4, and 4-4 by 50-60%, but did not affect isoenzymes 1-1 and 1-2. The ability of halothane to diminish hepatic glutathione S-transferase activity in vivo may in part reflect the time-dependent inhibition of glutathione S-transferase isoenzymes containing the 3- and 4-subunits.
Ivanetich
K M
KM
Department of Medical Biochemistry, University of Cape Town Medical School, Observatory, South Africa.
Thumser
A E
AE
Harrison
G G
GG
D000758:Anesthesia; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006221:Halothane / Q000378:metabolism / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008099:Liver / Q000201:enzymology*; D008297:Male; D051381:Rats; D013997:Time Factors
D007527:Isoenzymes; D005982:Glutathione Transferase; D006221:Halothane