Early, selective and reversible suppression of cytochrome P-450-dependent monooxygenase of liver microsomes following the administration of low doses of carbon disulfide in mice.
The effects of carbon disulfide (CS2) on the liver microsomal drug-metabolizing enzyme system and other enzyme activities were studied 1 hr after the oral administration of 3-300 mg/kg of CS2 in mice. Considerable decreases in drug-metabolizing enzyme activities (such as hydroxylation of aniline, O-dealkylation of p-nitroanisole, 7-ethoxycoumarin and 7-ethoxyresorufin, and N-demethylation of N,N-dimethylaniline), NADPH-cytochrome P-450 reductase (but not NADPH-cytochrome c reductase), and P-450-associated peroxidase activities were already observed at 3 and 30 mg/kg of CS2, dose dependently. At the same dosage levels, the magnitudes of microsomal spectral changes induced by aniline and nicotinamide (type 2 substrates), but not those induced by hexobarbital and SKF-525A (type 1 substrates), were also reduced to a considerable extent. The degrees of these alterations were all greater than that of the measurable loss of P-450 content, i.e. the loss of functional activity of P-450 was much greater than simply expected from the apparent decrease in the hemoprotein content. Cytochrome b5 content and NADH-ferricyanide reductase activity were unchanged at 30 and 300 mg/kg of CS2, although NADH-cytochrome c reductase activity was increased at the latter dose. The following enzyme activities did not change significantly at up to 300 mg/kg of CS2: flavin-containing monooxygenase, UDP-glucuronyl transferase, glucose-6-phosphatase and heme oxygenase in microsomes, and glutathione S-transferases in the soluble fraction. Microsomal conjugated diene levels and liver glutathione content were also unchanged. These observations support the theory that P-450 is a sensitive and selective site for CS2 action, where CS2 itself is bioactivated. It was also shown that the loss of P-450 was reversible after a single, or repeated, administration of CS2.
D000818:Animals; D002246:Carbon Disulfide / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System; D004305:Dose-Response Relationship, Drug; D006420:Hemeproteins / Q000032:analysis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D010105:Oxygenases / Q000032:analysis / Q000037:antagonists & inhibitors*; D013997:Time Factors
D006420:Hemeproteins; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D002246:Carbon Disulfide