Deletion of microsomal cytochrome b5 profoundly affects hepatic and extra-hepatic drug metabolism

We recently demonstrated that cytochrome b5 plays an important in vivo role in hepatic cytochrome P450 (P450) function (Finn et al., J. Biol. Chem. (2008)). We have now generated a model where cytochrome b5 has been deleted in all tissues (BCN; cytochrome b5 complete null), which surprisingly results in a viable mouse in spite of the putative in vivo roles of this protein in lipid and steroid hormone metabolism, and the reduction of methemoglobin. In contrast to the liver-specific deletion, complete deletion of cytochrome b5 leads to a neonatal increase in the expression of many hepatic P450s, at both the protein and mRNA level. In extra-hepatic tissues, some changes in P450 expression were also observed, which were isoform-dependent. In vitro cytochrome P450 activities in liver, kidney, lung and small intestine of BCN mice were determined for a range of model substrates and probe drugs; a profound reduction in the metabolism of some substrates, particularly in lung, kidney and small intestine was observed. In vivo, the metabolism of metoprolol was significantly altered in BCN mice, in contrast to the previous finding in the liver-specific cytochrome b5 deletion, suggesting that extra-hepatic cytochrome b5 plays a significant role in its disposition. Testicular Cyp-17 hydroxylase and lyase activities were also significantly reduced by cytochrome b5 deletion, leading to significantly lower levels of testicular testosterone. The BCN mouse provides an additional model system with which to further investigate the functions of cytochrome b5, particularly in extra-hepatic tissues