In vitro and in vivo effect of methyl isocyanate on rat liver mitochondrial respiration.
Previous work has shown that irrespective of the route of exposure methyl isocyanate (MIC) caused acute lactic acidosis in rats (Jeevaratnam et al., Arch. Environ. Contam. Toxicol. 19, 314-319, 1990) and the hypoxia was of stagnant type due to tissue hypoperfusion resulting from hypovolemic hypotension in rabbits administered MIC subcutaneously (Jeevarathinam et al., Toxicology 51, 223-240, 1988). The present study was designed to investigate whether MIC could induce histotoxic hyperoxia through its effects on mitochondrial respiration. Male Wistar rats were used for liver mitochondrial and submitochondrial particle (SMP) preparation. Addition of MIC to tightly coupled mitochondria in vitro resulted in stimulation of state 4 respiration, abolition of respiratory control, decrease in ADP/O ratio, and inhibition of state 3 oxidation. The oxidation of NAD(+)-linked substrates (glutamate + malate) was more sensitive (five- to sixfold) to the inhibitory action of MIC than succinate while cytochrome oxidase remained unaffected. MIC induced twofold delay in the onset of anerobiosis, and cytochrome b reduction in SMP with NADH in vitro confirms inhibition of electron transport at complex I region. MIC also stimulated the ATPase activity in tightly coupled mitochondria while lipid peroxidation remained unaffected. As its hydrolysis products, methylamine and N,N'-dimethylurea failed to elicit any change in vitro; these effects reveal that MIC per se acts as an inhibitor of electron transport and a weak uncoupler. Administration of MIC sc at lethal dose caused a similar change only with NAD(+)-linked substrates, reflecting impairment of mitochondrial respiration at complex I region and thereby induction of histotoxic hypoxia in vivo.
Jeevaratnam
K
K
Defence Research and Development Establishment, Gwalior, India.
Vidya
S
S
Vaidyanathan
C S
CS
D000244:Adenosine Diphosphate / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D003485:Cyanates / Q000008:administration & dosage / Q000494:pharmacology*; D004579:Electron Transport / Q000187:drug effects; D007279:Injections, Subcutaneous; D017953:Isocyanates; D008297:Male; D008744:Methylamines / Q000494:pharmacology; D008782:Methylurea Compounds / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009243:NAD / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
D003485:Cyanates; D017953:Isocyanates; D008744:Methylamines; D008782:Methylurea Compounds; D009243:NAD; D000244:Adenosine Diphosphate; C027451:methylamine; C008461:methyl isocyanate; D010088:Oxidoreductases; D000251:Adenosine Triphosphatases; C018275:1,1-dimethylurea