Pharmacogenomics of human P450 oxidoreductase

Cytochrome P450 enzymes are responsible for metabolism of drugs and xenobiotics in the liver and biosynthesis of steroid hormones in the reproductive tissues. There are two distinct types of P450 enzymes; type 1 enzymes are found in mitochondria and type 2 enzymes are present in endoplasmic reticulum (also known as microsomal fraction). Of the total 57 human P450 enzymes 50 are of microsomal variety and rely on electron transfer from the cofactor NADPH through a unique enzyme NADPH P450 oxidoreductase (also known as POR or CPR). The majority of drugs in clinical use are metabolized by a small number of P450 enzymes. Regulation of steroidogenesis in humans is carried out by four P450 enzymes: P450scc, P450C17, P450C21 and P450C19 (aromatase). All these enzymes except for P450scc are of microsomal, type 2 and require POR for activity. P450 enzymes have been studied extensively due to their role in drug and steroid metabolism and genetic variations in drug metabolizing P450s have been found to be responsible for altered drug responses. A genechip (Amplichip P450) (microarray) test to screen for variations in two of these P450s (2C19 and 2D6) had recently been approved for clinical use. We have shown that mutations in POR can cause endocrine dysfunctions like female infertility and severe cases of POR deficiency resemble a group of congenital disorder known as Antley-Bixler Syndrome. A recently completed population genetic variation study known as HapMap project as well as sequencing of POR by independent investigators have found several variations in the human POR gene. We have established functional studies of POR variants by testing the electron transfer to cytochrome c and another more specific test of the POR mediated 17-hydroxylation and 17,20 lyase activities of P450C17. Since all 50 microsomal P450 enzymes depend on POR for electron supply, we are putting forward the hypothesis that defects in POR could cause disorders in hepatic drug and xenobiotic metabolism as well as affect the functions of all steroid metabolizing microsomal P450 enzymes. Different P450 enzymes have variable affinities for POR and mutations / polymorphisms in POR could have different effect on different P450 enzymes. A change in activities of P450 by variant POR will lead to changes in effective/toxic dosages of drugs. In the past sequencing of P450 genes sometimes could not explain the reasons for defective drug/steroid metabolism. POR also supports heme degrading enzyme heme oxygenase and can reduce cytochrome b5, a component of many P450 mediated reactions. We plan to study the role of POR variations in human health and diseases. Findings from these studies will provide a better understanding of the endocrine disorders caused by POR variations and polymorphisms in human population and establish the pharmacogenomic role of POR variants in drug and steroid metabolism.

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