Chronic administration of the oral hypoglycaemic agent diphenyleneiodonium to rats. An animal model of impaired oxidative phosphorylation (mitochondrial myopathy).
Daily subcutaneous administration of the oral hypoglycaemic agent, diphenyleneiodonium at a low dose (1.5 mg/kg body weight) over a 4-5 week period resulted in a normoglycaemic stable animal model of impaired oxidative phosphorylation in the rat. Diphenyleneiodonium specifically inhibits NAD-linked mitochondrial oxidation [Bloxham, Biochem. Soc. Trans. 7, 103 (1979)], and in isolated mitochondrial preparations from heart, soleus and gastrocnemius muscle and liver from treated animals NAD-linked respiration was reduced by 40% or more of mean control values. Brain and kidney mitochondria isolated from the treated group had similar rates of NAD-linked respiration to their respective control values. The activity of NADH-ferricyanide reductase was significantly reduced in all tissues tested, even in the isolated brain and kidney mitochondria where the activity in these tissues was 60-75% of control values. This suggests that at least 40% of Complex I activity must be inhibited before there is a decline in NAD-linked mitochondrial respiration. This paper discusses the use of diphenyleneiodonium as a means of establishing an animal model of the human disease state, termed mitochondrial myopathy.
Cooper
J M
JM
Department of Biochemistry, Medical College of St. Bartholomew's Hospital, University of London, U.K.
Petty
R K
RK
Hayes
D J
DJ
Morgan-Hughes
J A
JA
Clark
J B
JB
D000284:Administration, Oral; D000818:Animals; D003580:Cytochromes / Q000032:analysis; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000633:toxicity*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism; D009135:Muscular Diseases / Q000139:chemically induced*; D009243:NAD / Q000378:metabolism; D009861:Onium Compounds / Q000633:toxicity*; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D011768:Pyruvate Dehydrogenase Complex / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains
D003580:Cytochromes; D007004:Hypoglycemic Agents; D009861:Onium Compounds; D011768:Pyruvate Dehydrogenase Complex; D009243:NAD; C007517:diphenyleneiodonium