Possible mechanism for species difference on the toxicity of pivalic acid between dogs and rats.
In a high dose toxicity study of pivalic acid (PA), PA caused skeletal muscle disorder in dog, and a significant increase of pivaloyl carnitine (PC) was observed in canine muscle, but not in rat muscle. In order to understand species difference of the toxicity of PA, we compared the in vitro metabolism of PA among dog, rat and rabbit, especially focussing on the carnitine conjugate. Canine muscle showed low, but significant carnitine conjugating activity, while that of rat was negligible. Canine kidney mitochondria had significant activity in the pivaloyl CoA synthesis (7 nmol/mg protein/h), but muscle mitochondria showed only trace activity. Both kidney and muscle mitochondria displayed similar carnitine acyltransferase activity (2-3 nmol/mg protein/h) towards pivaloyl CoA. On the other hand, with respect to the activity of carnitine acyltransferase in the reverse direction using PC as substrate, canine muscle mitochondria showed higher activity than that of kidney mitochondria. This means that PC is not the final stable metabolite, but is converted easily to pivaloyl CoA in canine muscle. These results suggest one of the possible mechanisms for canine selective muscle disorder to be as follows. Only canine muscle can metabolize PA to its carnitine conjugate slowly, but significantly. In canine muscle, PC is not the final stable metabolite; it is easily converted to pivaloyl CoA. As carnitine conjugation is thought to be the only detoxification metabolic route in canine muscle, under certain circumstances such as carnitine deficiency, the risk of exposure with toxic pivaloyl CoA might increase and the CoASH pool in canine muscle might be exhausted, resulting in toxicity in canine muscle.
Yamaguchi
Toshiro
T
Drug Metabolism and Pharmacokinetics, Developmental Research Laboratories, Shionogi and Co., Ltd. Toyonaka, Osaka 561-0825, Japan. toshiro.yamaguchi@shionogi.co.jp
Nakajima
Yoshitsugu
Y
Nakamura
Yutaka
Y
D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000633:toxicity*; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D004285:Dogs; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D010421:Pentanoic Acids / Q000378:metabolism / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D000214:Acyl Coenzyme A; D000900:Anti-Bacterial Agents; D010421:Pentanoic Acids; C005566:pivalic acid; C054040:pivaloylcarnitine; D002331:Carnitine