Effect of carbon monoxide on the cytochrome p‐450‐mediated activation of 4‐ipomeanol by the isolated perfused rabbit lung

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Abstract
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.

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