CYP4B1 activates 4-ipomeanol in rat lung.
Inhibition of pulmonary CYP4B1 activity by pretreatment of rats with p-xylene decreased the ability of lung microsomes to N-hydroxylate 2-aminofluorene and prevented the lung damage normally seen after dosing with ipomeanol. The toxicity of ipomeanol, as assessed by acute lethality, was decreased by a factor of eight. In contrast, induction of CYP1A1 by Aroclor or beta-naphthoflavone, or inhibition of CYP2B1 by O,O,S-trimethyl-phosphorodithioate, as assessed by measurement of lung microsomal dealkylation of ethoxyresorufin or pentoxyresorufin, did not change ipomeanol toxicity. A polyclonal antibody raised against CYP4B1 prevented the covalent binding of [14C]-ipomeanol to lung microsomal protein in vitro. Antibodies raised against the other major P450 isozymes of rat lung, CYP2B1 and CYP1A1, had no effect on this binding. Aroclor, beta-naphthoflavone, and O,O,S-trimethylphosphorodithioate failed to affect binding of radiolabeled ipomeanol in vivo, but pretreatment with p-xylene resulted in a significant reduction in this binding. The CYP4B1 substrate 2-aminofluorene, when dosed to rats, caused a sixfold decrease in ipomeanol toxicity. These results indicate that in the rat, unlike the rabbit, pulmonary bioactivation of ipomeanol is predominantly dependent upon CYP4B1.
Verschoyle
R D
RD
MRC Toxicology Unit, MRC Laboratories, Carshalton, Surrey, United Kingdom.
Philpot
R M
RM
Wolf
C R
CR
Dinsdale
D
D
D000818:Animals; D001711:Biotransformation; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D005260:Female; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D007928:Lethal Dose 50; D008168:Lung / Q000201:enzymology*; D008861:Microsomes / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D013729:Terpenes / Q000493:pharmacokinetics* / Q000633:toxicity; D014118:Toxins, Biological / Q000493:pharmacokinetics*; D014992:Xylenes / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; D013729:Terpenes; D014118:Toxins, Biological; D014992:Xylenes; C031286:4-xylene; D003577:Cytochrome P-450 Enzyme System; C001470:4-ipomeanol