CYP4B1 Activates 4-Ipomeanol in Rat Lung

• Published in: Toxicology and applied pharmacology Vol. 123; no. 2; pp. 193 - 198
• Main Authors: Verschoyle, R.D., Philpot, R.M., Wolf, C.R., Dinsdale, D.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.12.1993; Elsevier
• Subjects: ACTIVIDAD ENZIMATICA; ACTIVITE ENZYMATIQUE; Animals; BATATA; Biological and medical sciences; Biotransformation; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - physiology; Female; Ipomoea batatas; Isoenzymes - antagonists & inhibitors; Isoenzymes - physiology; Lethal Dose 50; Lung - enzymology; Medical sciences; METALLOPROTEINE; METALPROTEINAS; Microsomes - enzymology; ORGANITE CELLULAIRE; ORGANULOS CITOPLASMICOS; PATATE DOUCE; Plant poisons toxicology; POUMON; PULMONES; RAT; RATA; Rats; Rats, Wistar; SUBSTANCE TOXIQUE; SUSTANCIAS TOXICAS; Terpenes - pharmacokinetics; Terpenes - toxicity; TERPENOIDE; TERPENOIDOS; TOXICIDAD; TOXICITE; Toxicology; Toxins, Biological - pharmacokinetics; Xylenes - pharmacology; Terpenoid; Rat; Respiratory disease; Isozyme; Cytochrome P450; Lung; Rodentia; Furan derivatives; Metabolism toxicity relation; Vertebrata; Mammalia; Animal; Plant origin; Mechanism of action
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.1993.1237

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 β-naphthoflavone, or inhibition of CYP2B1 by O,O,S-trimethylphosphorodithioate, 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, β-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.