Evidence for the Clara cell as a site of cytochrome P450-dependent mixed-function oxidase activity in lung

Abstract

THE cellular localisation of pulmonary mixed-function oxidase (MFO) activity has aroused considerable interest, especially because of the increasing incidence of lung disease of environmental origin—including cancers—and the realisation that many chemical toxins and carcinogens require MFO-catalysed activation. The precise identification of pulmonary cellular populations possessing MFO activity has previously met with little success, however, probably because of the complexity and heterogeneity of the lung, which has been estimated to contain over 40 different specific cell types¹. In this communication I describe studies with the pulmonary toxin, 4-ipomeanol (1-[3-furyl]-4-hydroxypentanone)², which indicate that a highly reactive metabolite of this naturally occurring furan derivative is preferentially formed and covalently bound in pulmonary non-ciliated bronchiolar (Clara)³ cells, leading to their necrosis. Since previous studies⁴ have established that the toxic metabolite formed in vivo during cytochrome P450-dependent oxidative metabolism of 4-ipomeanol is formed in situ in the lung, and does not reach the lung by way of the circulation, the present results indicate that the Clara cell is a primary locus of P450-dependent MFO enzymes in lung.