Dennis R Koop, Ph.D.
The cytochrome P450 system is essential in most organisms for the biosynthesis of endogenous compounds such as steroids, fatty acids, prostaglandins and pheromones. However, the largest number of P450 substrates are foreign chemicals that include drugs, plant metabolites, environmental pollutants and food additives. In general, the role of P450 is to detoxify chemicals and increase elimination from the body. However, in some cases the oxidized products can initiate cell toxicity, including chemical carcinogenesis, mutagenesis and teratogenesis. The detrimental properties of this enzyme family underscore the importance of understanding the regulation of the individual members of the gene family.Research in my laboratory is focused on characterizing the regulation and catalytic activity of P450 2E1 (CYP2E1), and examining the effect of antioxidants on stress signaling pathways and P450-dependent metabolism. The level of CYP2E1 is increased by alcohol consumption, and it is hypothesized that many ethanol-associated toxicities are due to the induction of this enzyme in hepatic and extrahepatic tissues. For example, an increased hepatotoxicity of acetaminophen is thought to be due to metabolism of this commonly used over-the-counter pain medication to a reactive metabolite by higher levels of CYP2E1. The induction of CYP2E1 also is associated with an increased generation of active oxygen species that can initiate cellular damage. Since the degree of damage is related to the level of the enzyme, it is important to find those factors that control its intracellular concentration and to identify compounds that can alter its metabolic activity and expression. The research in my laboratory utilizes ce ll lines expressing the normal CYP2E1 and selectively modified forms of the enzyme to identify those regions important in its degradation. In addition, the expression is monitored in genetic models of iron overload where induction of CYP2E1 could exacerbate drug-induced toxicity. The effect of constituents of natural products such as those found in herbal tinctures and alcoholic beverages on P450 dependent expression and metabolism are also being investigated. The metabolic activity of CYP2E1 and other P450s toward endogenous compounds such as lipids, sterols and steroids is being investigated using state-of-the art LC/MS.
"A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer,"
"Analysis of tacrolimus and creatinine from a single dried blood spot using liquid chromatography tandem mass spectrometry,"
"Threshold levels of ABL tyrosine kinase inhibitors retained in chronic myeloid leukemia cells determine their commitment to apoptosis,"
"Effect of the ethinylestradiol/levonorgestrel combined oral contraceptive on the activity of cytochrome P4503A in obese women,"
"Naloxone pro-drug rescues morphine induced respiratory depression in Sprague-Dawley rats,"