The prediction of benzo[a]pyrene clearance by rat liver and lung from enzyme kinetic data

The metabolic clearance of circulating benzo[a]pyrene (B[a]P) by liver and lung of control and 3-methylcholanthrene (3MC)-pretreated rats was predicted according to the perfusion-limited model from apparent enzyme kinetic constants determined in microsomal incubations. These predictions were tested in isolated organs perfused at normal organ flow. From microsomal incubations the apparent enzyme kinetic constants of B[a]P metabolism were determined. The apparent Km of liver microsomes was decreased 100 times by pretreatment with 3MC, while the Km of lung microsomes remained at about 0.2 microM. Maximal velocity of B[a]P metabolism was much greater in microsomes from liver than in those from lung of both control and 3MC-pretreated rats. Liver was found to have a far greater capacity for B[a]P metabolism (intrinsic free clearance) than lung. However, this large disparity was not evident in the predicted clearances. Perfused organs had B[a]P clearances very close to those predicted from the model. At normal (in vivo) organ flows, control rat lung had a clearance of 1.0 +/- 0.1 ml/min, whereas liver had a clearance of 5.9 +/- 0.2 ml/min. Corresponding clearances in organs from 3 MC-pretreated rats were 8.9 +/- 0.5 and 6.7 +/- 0.6 ml/min for lung and liver, respectively. Small discrepancies between predicted and observed values could not be explained by non-uniform distribution of B[a]P or shunting of flow. These results suggest that enzyme kinetic data can be used to assess accurately the ability of lung and liver to clear xenobiotic compounds such as B[a]P and that, despite the great disparity in their metabolic capacity, under certain conditions these two organs may function equally well in the removal of circulating compounds from the blood.