Cytochrome P4502A‐Mediated Cownarin 7‐Hydroxylation and Testosterone Hydroxylation in Mouse and Rat Lung

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Abstract
Pulmonary coumarin 7‐hydroxylase, testosterone hydroxylase and other P450‐mediated activities were compared in the mouse and rat. Coumarin 7‐hydroxylase activity was 20 pmol/mg/min. in mouse and 4 pmol/mg/min. in rat lung microsomes. Liver values were 180 (mouse) and 1 (rat) pmol/mg/min. Kmvalues of rat and mouse lung coumarin 7‐hydroxylase were about 1 μM whereas the rat liver Kmvalue was > 100 μM. Phenobarbital and 3‐methylcholanthrene did not affect rat lung (or liver) coumarin 7‐hydroxylase activity. Anti‐Cyp2a‐5 antibody effectively inhibited mouse and rat lung coumarin 7‐hydroxylase and testosterone 15α‐hydroxylations but failed to block these activities in the rat liver. In immunoblot analysis anti‐Cyp2a‐5 antibody recognized the 50‐kDa Cyp2a‐4/5 protein in mouse lung microsomes. A P450 protein co‐migrating with Cyp2a‐5 was also detected in rat lung microsomes.Cyp2a‐5cDNA probe hybridized with a 1.8‐kb mRNA species in rat lung RNA fraction. The hybridization signal was not increased by 3‐methylcholanthrene or phenobarbital. These data suggest that the mouse lung expresses Cyp2a‐5 which differs from the liver enzyme only in its regulation and that the rat lung contains a P450 isoform(s) belonging to the 2A subfamily which may be orthologous with the mouse Cyp2a‐415 catalyzing coumarin 7‐hydroxylase and testosterone 15a‐hydroxylase activities. The recently reported rat lung CYP2A3 (Kimuraet al.)gene product is a candidate for the observed coumarin 7‐hydroxylase activity in the rat lung.

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