The mechanism of the suicidal, reductive inactivation of microsomal cytochrome P-450 by carbon tetrachloride

Effect of Picroliv on impaired hepatic mixed-function oxidase system in carbon tetrachloride-intoxicated rats

“…Using electron-spin resonance measurements, the formation of trichloromethyl free radicals from CCl 4 has been demonstrated in isolated microsomes and in intact liver tissues [Ko et al, 1993] and is responsible for hepatotoxicity including damage to MFO system. The present study has also corroborated evidence for an impaired hepatic MFO system during CCl 4 -induced hepatotoxicity reported earlier [Fuzimoto and Plaa, 1961;Megirian, 1964;Manno et al, 1988]. There has been a reduction in the activities of various microsomal enzymes related to drug metabolism.…”

“…Carbon tetrachloride (CCl 4 ) toxication also causes destruction of cytochrome P-450 and heme, as well as decreased activity of cytochrome P-450-dependent and other drug-metabolising enzymes in the liver [Fuzimoto and Plaa, 1961;Megirian, 1964;Manno et al, 1988]. This communication deals with the status of hepatic MFO system and associated activities in rats intoxicated with CCl 4 , as well as the effect of pretreatment with Picroliv on these changes.…”

Improved Risk Estimates for Carbon Tetrachloride

“…This result suggests that CYP450 inactivation resulting from CCl 4 metabolism accounts for the discrepancies between activity and protein levels. Human CYP450s appear to be less susceptible than those of rats to inactivation by CCl 4 , such that approximately 200 CCl 4 molecules must be metabolized per inactivated CYP450 enzyme in humans, but only 26 CCl 4 molecules must be metabolized in rats (Manno et al, 1988(Manno et al, , 1992. Therefore, CYP450 inactivation by CCl 4 in humans may be less significant than in rats, and induction of catalytic activity could be correspondingly greater.…”

Heme oxygenase‐1: a new drug target in oxidative tissue injuries in critically ill conditions

“…Coincident with the increase in microsomal heme concentration, there was a concurrent decline in hepatic CYP content after CCl 4 treatment . It is known that hepatic CYP undergoes significant destruction during the metabolism of CCl 4 [Clarke and Lui, 1986;Manno et al, 1988]. Thus, it is likely that heme may be rapidly released from CYP when CCl 4 is metabolized, and is reflected in an increase in intracellular ''free heme'' concentration (Fig.…”