Metabolic disorders caused by mutations and polymorphisms in P450 oxidoreductase
Most drugs and xenobiotics are metabolized by a small number of hepatic cytochrome P450 enzymes. All drug metabolizing P450 enzymes receive electrons from NADPH through a single flavoprotein known as NADPH-P450 reductase.
We have recently identified mutations in NADPH P450 reductase from patients with disordered steroidogenesis. Polymorphisms in the drug metabolizing enzymes, especially cytochrome P450s are well known to be responsible for variations in drug responses. My preliminary work on mutant and polymorphic P450 reductase suggests that many drug metabolizing P450 enzymes are severely affected by an abnormal P450 reductase enzyme. Since all liver P450 enzymes need P450 reductase for activity, it is seems likely that changes in P450 reductase may produce drug responses that are phenotypically similar to one or more cytochrome P450 mutations / polymorphisms. As an example, in the first report of P450 reductase mutations, the disease profile of hormonally impaired patients suggested a defect in P450c17 or P450c21 but no mutation in any of these enzymes was found and it was the defective P450 reductase that produced a phenotypic response similar to defective P450c17 and P450c21. Sequencing data from normal population has revealed several variants of NADPH P450 reductase enzyme. These P450 reductase variants are being tested for the electron transfer activities towards various cytochrome P450 enzymes. First set of P450 reductase mutations had been tested for activity towards P450c17 and aromatase (CYP19A1). Recently we have tested effects of P450 reductase mutations on human heme oxygenase (HO-1) and CYP3A4 activities.
PD Dr. Amit V Pandey
Pediatric Endocrinology, Diabetology and Metabolism,
KIKL C837, Inselspital
University Children's Hospital Bern,
Freiburgstrasse 15, 3010 Bern
Tel: +41 31 632 9637 (Office)
+41 31 632 9527 (Lab)