Dehydromonocrotaline inhibits mitochondrial complex I. A potential mechanism accounting for hepatotoxicity of monocrotaline.
Monocrotaline is a pyrrolizidine alkaloid present in plants of the Crotalaria species, which causes cytotoxicity and genotoxicity, including hepatotoxicity in animals and humans. It is metabolized by cytochrome P-450 in the liver to the alkylating agent dehydromonocrotaline. We evaluated the effects of monocrotaline and its metabolite on respiration, membrane potential and ATP levels in isolated rat liver mitochondria, and on respiratory chain complex I NADH oxidase activity in submitochondrial particles. Dehydromonocrotaline, but not the parent compound, showed a concentration-dependent inhibition of glutamate/malate-supported state 3 respiration (respiratory chain complex I), but did not affect succinate-supported respiration (complex II). Only dehydromonocrotaline dissipated mitochondrial membrane potential, depleted ATP, and inhibited complex I NADH oxidase activity (IC50=62.06 microM) through a non-competitive type of inhibition (K(I)=8.1 microM). Therefore, dehydromonocrotaline is an inhibitor of the activity of respiratory chain complex I NADH oxidase, an action potentially accounting for the well-documented monocrotaline's hepatotoxicity to animals and humans. The mechanism probably involves change of the complex I conformation resulting from modification of cysteine thiol groups by the metabolite.
Mingatto
Fábio E
FE
Laboratório de Bioquímica, Faculdade de Zootecnia, Universidade Estadual Paulista Júlio de Mesquita Filho, Campus de Dracena, 17900-000 Dracena, SP, Brazil. fmingatto@dracena.unesp.br
Dorta
Daniel J
DJ
dos Santos
Aline B
AB
Carvalho
Ivone
I
da Silva
Carlos H T P
CH
da Silva
Vinícius B
VB
Uyemura
Sérgio A
SA
dos Santos
Antonio C
AC
Curti
Carlos
C
D000255:Adenosine Triphosphate / Q000378:metabolism; D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology*; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D016686:Monocrotaline / Q000031:analogs & derivatives* / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013367:Submitochondrial Particles / Q000187:drug effects / Q000201:enzymology
D000477:Alkylating Agents; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; C014114:monocrotaline pyrrole; D016686:Monocrotaline; D000255:Adenosine Triphosphate; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I