Effects of 3-methylcholanthrene on covalent binding and toxicity of 4-ipomeanol in inducible and non-inducible (B6D2) mice.
The effects of 3-methylcholanthrene (MC) on the covalent binding and toxicity of 4-ipomeanol (1-(3-furyl)-4-hydroxypentanone, IPO) were studied in (C57BL/6N)(DBA/2N)F1 X DBA/2N backcross (B6D2)D2) mice previously segregated into relatively "inducible" or "non-inducible" groups based on zoxazolamine (2-amino-5-chlorobenzoxazole, ZOX) paralysis times following MC treatment. MC decreased the covalently bound IPO metabolite(s) both in the lungs and in the kidneys of "inducible" and "non-inducible" mice when compared to controls not pretreated with MC. On the other hand, concentrations of covalently bound IPO metabolite(s) in liver were increased in "inducible" mice and decreased in "non-inducible" mice by MC pretreatment when compared to non-pretreated heterogenous mice. Associated with MC pretreatment was a significant decrease in the acute lethality of IPO both in the "inducible" and in the "non-inducible" mice when compared to nonpretreated control animals (LD50: 213 +/- 2, 140 +/- 14 and 14 +/- 4 mg/kg, respectively). Hepatic necrosis occurred frequently in the "inducible" mice and occasionally in the "non-inducible" mice given large IPO doses near the respective LD50-values. Hepatic necrosis was never observed in non-pretreated mice receiving near lethal doses of IPO. These results support previous studies indicating that reactive IPO metabolites binding to extrahepatic tissues are formed in situ and do not reflect binding of blood-borne metabolites formed in the liver.
D000818:Animals; D003603:Cytotoxins / Q000633:toxicity*; D004790:Enzyme Induction; D007928:Lethal Dose 50; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000187:drug effects; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D013729:Terpenes / Q000378:metabolism / Q000633:toxicity*
D003603:Cytotoxins; D013729:Terpenes; D008748:Methylcholanthrene; C001470:4-ipomeanol