Effect of carbon monoxide on the cytochrome P-450-mediated activation of 4-ipomeanol by the isolated perfused rabbit lung.
4-Ipomeanol is a naturally occurring toxin that induces lesions in the lung following its activation to an alkylating metabolite by the pulmonary cytochrome P-450 system. The aim of this study was to determine if an environmentally relevant concentration of carbon monoxide could inhibit the activation of 4-ipomeanol and prevent the associated toxic sequelae in the isolated perfused rabbit lung. The lungs of male New Zealand rabbits were removed and perfused with [14C]-4-ipomeanol for 2 h starting with an initial concentration of 0.1 mM. Lungs were ventilated with either air (control) or 7.5% CO/20% O2. 4-Ipomeanol-derived covalent binding was identical in the control and carbon monoxide treatment groups. Lungs perfused with 4-ipomeanol and ventilated with air or 7.5% CO/20% O2 both displayed alveolar type II cell hyperplasia and alveolar macrophage infiltration. Surprisingly, there was no histological evidence of Clara cell damage in any of the 4-ipomeanol-perfused lungs. These results suggest that the isozymes of pulmonary cytochrome P-450 that act in concert to metabolize 4-ipomeanol are relatively insensitive to inhibition by carbon monoxide.
Trela
B A
BA
Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
Carlson
G P
GP
Turek
J
J
Rebar
A
A
Mathews
J M
JM
D000818:Animals; D001711:Biotransformation; D002248:Carbon Monoxide / Q000494:pharmacology*; D002249:Carbon Monoxide Poisoning / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010477:Perfusion; D011485:Protein Binding; D011817:Rabbits; D013729:Terpenes / Q000378:metabolism* / Q000633:toxicity; D014118:Toxins, Biological / Q000378:metabolism
D013729:Terpenes; D014118:Toxins, Biological; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; C001470:4-ipomeanol