4-Ipomeanol (IPO) is a furan derivative that is metabolized to an alkylating agent by Clara cells in vivo, leading to Clara cell necrosis (Nature 269:713 1977). In vitro experiments revealed that V max per nanomoles of cytochrome P-450 for the formation of alkylating metabolite of IPO was about 10-20 times greater in pulmonary than in hepatic microsomes. Interestingly, the activation of IPO by pulmonary microsomes was dependent upon not only carbon monoxide sensitive cytochrome P-450 but also cytochrme b5. An antibody prepared against purified cytochrome b5 from rat liver microsomes, which was inactive gainst TPNH cytochome c reductase, almost completely inhibited the TPNH mediated metabolism of IPO by pulmonary but not hepatic microsomes. Preincubation of the anticytochrome b5 with purified cytochrome b5 reversed its inhibitory effect on pulmonary microsomal metabolism of IPO, suggesting that the inhibition was dued to a specific effect of the antibody on microsomal cytochrome b5.