Question

what is the relationship between cytochrome p450 and nadh-cytochrome b5 reductase 3 in APAP metabolism?

Answer 1

The interactions between the protein components of xenobiotic metabolizingt the cytochrome P450 system, CYP6A1, P450 reductase & cytochrome b₅ from the house fly is been . CYP6A1 activityhat is determined by concentration of the CYP6A1-P450 reductase complex, not concerned with type of protein present in excess. Both holo- and apo-b₅ stimulated CYP6A1 heptachlor epoxidase and steroid hydroxylase activities and influence the regioselectivity of testosterone hydroxylation. The conversion of CYP6A1 to P420 type was reuduced by the addiing of apo-b₅. The effects of cytochrome b₅ may involve allosteric type of modification of the P450 enzyme that will modify the conformation of the active site. The overall stoichiometry of the P450 reaction is dependent on the substrate . High uncoupling of CYP6A1 was seen with generation of hydrogen peroxide, in excess over the concomitant testosterone hydroxylation or heptachlor epoxidation. Inclusion of cytochrome b₅ in the reconstituted system improved efficiency of oxygen consumption and electron utilization from NADPH, or coupling of the P450 reaction. Depending on the reconstitution conditions, coupling efficiency ranges between from 8 to 25% for heptachlor epoxidation, and from 11 to 70% for testosterone hydroxylation. Because CYP6A1 is a P450 involved in insecticide resistance, this suggests that xenobiotic metabolism by constitutively overexpressed P450s may be linked to significant oxidative stress in the cell that may carry a cost of fitness.

NADPH cytochrome P450 reductase (CPR) and the cytochrome-b₅ (b₅) along with the NADH-b₅ reductase (b₅R) play maor roles in cytochrome P450 3A-mediated drug metabolism via electron transfer. But, it is not clear right now whether variability in expression of these accessory proteins adds up to the known interindividual variability in CYP3A activity.