Objectives—CYP3A4 receives electrons from P450 oxidoreductase (POR) to metabolize about
50% of clinically used drugs. There is substantial inter-individual variation in CYP3A4 catalytic
activity that is not explained by CYP3A4 genetic variants. CYP3A4 is flexible and distensible,
permitting it to accommodate substrates varying in shape and size. To elucidate mechanisms of
variability in CYP3A4 catalysis, we examined the effects of genetic variants of POR, and explored
the possibility that substrate-induced conformational changes in CYP3A4 differentially affect the
ability of POR variants to support catalysis.