The pulmonary clara cell as a target for toxic chemicals requiring metabolic activation; studies with carbon...

Oral administration of carbon tetrachloride to rats or mice caused striking decreases in rat lung microsomal cytochrome P-450 and benzphetamine demethylase activity and in the enzyme-mediated covalent binding of 4-ipomeanol in preparations of rat and mouse lung microsomes, mouse lung slices and isolated whole-mouse lungs. Although it is not yet known whether cytochrome P-450 and benzphetamine demethylase activities are present in substantial amounts in more than one lung cell type in mice or rats, previous studies have indicated that cytochrome P-450 enzymes located in pulmonary bronchiolar Clara cells of these mediate the covalent binding of 4-ipomeanol to lung macromolecules. Histologic examinations of lungs of animals given doses of CCl4, orally or by inhalation, revealed striking morphologic changes in Clara cells, including severe dilation of endoplasmic reticulum and occasional cellular necrosis. Because of cytochrome P-450 enzymes are capable of mediating the formation of highly reactive and potentially toxic-free radicals from CCl4, the present results support the view that pulmonary Clara cells are susceptible to CCl4-induced injury due to their capacity to metabolically activate the chemical.