NADPH  Role in Cytochrome P450 Monooxygenase System

Monooxygenases (mixed-function oxidases) incorporate one atom from O2 into a substrate (creating a hydroxyl group), with the other atom being reduced to water (H2O). In the cytochrome P450 (CYP) monooxygenase system, NADPH provides the reducing equivalents required by this series of reactions (Fig. 1). This system performs different functions in two separate locations in cells. The overall reaction catalyzed by a CYP enzyme is : 

Figure 13.7 Cytochrome P450 (CYP) monooxygenase catalytic cycle (simplified). Electrons (e−) move from nicotinamide adenine dinucleotide phosphate (NADPH) to flavin adenine dinucleotide (FAD) to flavin adenine mononucleotide (FMN) of the reductase and then to the heme iron (Fe) of the microsomal CYP enzyme. [Note: In the mitochondrial system, e− move from FAD to an iron-sulfur protein and then to the CYP enzyme.]

where R may be a steroid, drug, or other chemical. [Note: CYP enzymes are actually a superfamily of related, heme-containing monooxygenases that participate in a broad variety of reactions. The P450 in the name reflects the absorbance at 450 nm by the protein.]
1. Mitochondrial system An important function of the CYP monooxygenase system found associated with the inner mitochondrial membrane is the biosynthesis of steroid hormones. In steroidogenic tissues, such as the placenta, ovaries, testes, and adrenal cortex, it is used to hydroxylate intermediates in the conversion of cholesterol to steroid hormones, a process that makes these hydrophobic compounds more water soluble . The liver uses this same system in bile acid synthesis  and the hydroxylation of cholecalciferol to 25-hydroxycholecalciferol ([vitamin D3] ), and the kidney uses it to hydroxylate vitamin D3 to its biologically active 1,25-dihydroxylated form.
2. Microsomal system The microsomal CYP monooxygenase system found associated with the membrane of the smooth endoplasmic reticulum (particularly in the liver) functions primarily in the detoxification of foreign compounds (xenobiotics). These include numerous drugs and such varied pollutants as petroleum products and pesticides. CYP enzymes of the microsomal system (for example, CYP3A4) can be used
to hydroxylate these toxins (phase I). The purpose of these modifications is two-fold. First, it may itself activate or inactivate a drug and second, make a toxic compound more soluble, thereby facilitating its excretion in the urine or feces. Frequently, however, the new hydroxyl group will serve as a site for conjugation with a polar molecule, such as glucuronic acid , which will significantly increase the compound’s solubility (phase II). [Note: Polymorphisms  in the genes for CYP enzymes can lead to differences in drug metabolism.]