The roles of cytochrome b5 in cytochrome P450 reactions

Cytochrome b5, a 17‐kDa hemeprotein associated primarily with the endoplasmic reticulum of eukaryotic cells, has long been known to augment some cytochrome P450 monooxygenase reactions, but the mechanism of stimulation has remained controversial. Studies in recent years have clarified this issue by delineating three pathways by which cytochrome b5 augments P450 reactions: direct electron transfer of both required electrons from NADH–cytochrome b5 reductase to P450, in a pathway separate and independent of NADPH–cytochrome P450 reductase; transfer of the second electron to oxyferrous P450 from either cytochrome b5 reductase or cytochrome P450 reductase; and allosteric stimulation of P450 without electron transfer. Evidence now indicates that each of these pathways is likely to operate in vivo.