Action of Ebselen on rat hepatic microsomal enzyme-catalyzed fatty acid chain elongation, desaturation, and drug biotransformation.
In the previous study, the organoselenium-containing anti-inflammatory agent, Ebselen, was found to disrupt both hepatic microsomal NADH- and NADPH-dependent electron transport chains. In the current investigation, we focus on the action of Ebselen on three separate metabolic reactions, namely, fatty acid chain elongation, desaturation, and drug biotransformation, which utilize reducing equivalents via these microsomal electron transport pathways. Both NADH-dependent and NADPH-dependent chain elongation reactions showed (i) that the condensation step was inhibited by Ebselen; all three substrates, palmitoyl CoA (16:0), palmitoleoyl CoA (16:1), and gamma-linolenyl CoA (18:3), were differentially affected by Ebselen; for example, the apparent Ki's of Ebselen for the condensation of 16:0, 16:1, and 18:3 in the absence of bovine serum albumin (BSA) preincubation were 7, 14, and 34 microM, and those in the presence of BSA preincubation were 35, 62, and 150 microM, respectively, supporting earlier data for multiple condensing enzymes; (ii) that the beta-ketoacyl CoA reductase-catalyzed reaction step which appears to receive electrons, at least in part, from the cytochrome b5 system, was also markedly inhibited by varying Ebselen concentrations; and (iii) that similar results were obtained with the dehydrase and the enoyl CoA reductase. Hence, each of the four component steps was significantly inhibited by Ebselen. Another important fatty acid biotransformation reaction, delta 9 desaturation of stearoyl CoA to oleoyl CoA, was significantly inhibited (90%) by 30 microM Ebselen. This effect appeared to be directly related to the NADH-dependent electron transport chain rather than to a direct action on the desaturase enzyme. Last, Ebselen also inhibited both aminopyrine and benzphetamine N-demethylations, two cytochrome P450-catalyzed reactions, in untreated rats, in rats on a high carbohydrate diet, and in phenobarbital-treated rats.
Laguna
J C
JC
Department of Pharmacology, University of Connecticut Health Center, Farmington 06032.
Nagi
M N
MN
Cook
L
L
Cinti
D L
DL
D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D001711:Biotransformation; D002384:Catalysis; D003573:Cytochrome b Group / Q000378:metabolism; D015786:Cytochromes b5; D004746:Enoyl-CoA Hydratase / Q000378:metabolism; D044943:Fatty Acid Desaturases / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism* / Q000493:pharmacokinetics; D054833:Isoindoles; D008297:Male; D008316:Malonyl Coenzyme A / Q000502:physiology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D016566:Organoselenium Compounds; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D012643:Selenium / Q000494:pharmacology*; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001393:Azoles; D003573:Cytochrome b Group; D005227:Fatty Acids; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D008316:Malonyl Coenzyme A; D015786:Cytochromes b5; D000429:Alcohol Oxidoreductases; D064431:3-Oxoacyl-(Acyl-Carrier-Protein) Reductase; D044943:Fatty Acid Desaturases; D013230:Stearoyl-CoA Desaturase; D000633:Aminopyrine N-Demethylase; C044121:short-chain beta-hydroxyacyl-CoA dehydrase; D004746:Enoyl-CoA Hydratase; D012643:Selenium