Disruption of rat hepatic microsomal electron transport chains by the selenium-containing anti-inflammatory agent Ebselen.
The influence of Ebselen, an organoselenium anti-inflammatory agent, on the two electron transport chains present in rat liver microsomes has been studied. At low micromolar concentrations, Ebselen markedly inhibited the flow of reducing equivalents from NADPH-cytochrome P450 reductase to both its natural electron acceptor, cytochrome P450, and its artificial electron acceptor, cytochrome c. Similarly, the microsomal NADH-cytochrome c reductase system consisting of cytochrome b5 and its flavoprotein, NADH-cytochrome b5 reductase, was also significantly inhibited by Ebselen. The inhibition appears to be due to the inability of the reduced pyridine nucleotide to transfer electrons to the flavin (FAD and/or FMN) in the flavoprotein reductase. This was shown with the purified NADPH-cytochrome P450 reductase, which in the presence of Ebselen was not converted to the semiquinone form following the addition of NADPH. The addition of Ebselen to a suspension of hepatic microsomes from either untreated or phenobarbital-treated rats did not result in any spectral change characteristic of type I, type II, or reverse type I.
Nagi
M N
MN
Department of Pharmacology, University of Connecticut Health Center, Farmington 06032.
Laguna
J C
JC
Cook
L
L
Cinti
D L
DL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003579:Cytochrome Reductases / Q000037:antagonists & inhibitors; D003573:Cytochrome b Group / Q000378:metabolism; D042966:Cytochrome-B(5) Reductase; D015786:Cytochromes b5; D004579:Electron Transport / Q000187:drug effects; D054833:Isoindoles; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D016566:Organoselenium Compounds; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D012643:Selenium / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001393:Azoles; D003573:Cytochrome b Group; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D009249:NADP; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D003579:Cytochrome Reductases; D042966:Cytochrome-B(5) Reductase; D012643:Selenium