Acute encephalopathy with hepatic steatosis induced by pantothenic acid antagonist, calcium hopantenate, in dogs

Abstract

ABSTRACT— In Japan, acute encephalopathy with hepatic steatosis resembling Reye's syndrome has been reported to occur after treatment with the pantothenic acid antagonist, calcium hopantenate. We studied the causal relationship and the pathogenesis in dogs. The agent was administered to seven dogs at increasing doses over a period of 8 weeks. Anorexia, vomiting, and diarrhea were common clinical findings. In four dogs, coma suddenly developed after the appearance of gastrointestinal signs. Three animals died during periods when they were not under direct observation. The effects of the agent appear to be related to dose. Laboratory findings representing significant changes at the time of coma included hypoglycemia, leukocytosis, hyperammonemia, hyperlactatemia, and elevated levels of serum transaminases. Microvesicular hepatic steatosis and mitochondrial abnormalities were consistent pathological findings. The hepatic mitochondria were enlarged and characterized by an increased number of cristae and the presence of crystalloid inclusions. In a second group of four dogs, pantothenic acid was given in addition to and in the same amount as calcium hopantenate at increasing doses over a period of 8 weeks. All four dogs survived the 8 weeks and only one developed mild anorexia. No significant biochemical changes were found and neither hepatic steatosis nor mitochondrial abnormalities were observed. The addition of pantothenic acid prevented the development of the disorder in the four animals. These results show that calcium hopantenate produces acute encephalopathy with hepatic steatosis in dogs, by inducing a deficiency of pantothenic acid. The hepatic mitochondrial changes of this reaction differ from those of Reye's syndrome.

Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence

“…Deficiency in pantothenic acid (vitamin B5) results in neurological dysfunction. Dogs treated with an antagonist of vitamin B5 that induces a deficiency of pantothenic acid developed an acute encephalopathy [144]. In humans, there is a rare genetic defect in the production of pantothenate kinase, an enzyme that is crucial in the synthesis of acetyl-CoA, which translates into inherited neurodegenerative diseases or neurodegeneration [145].…”

Chemical Knockout of Pantothenate Kinase Reveals the Metabolic and Genetic Program Responsible for Hepatic Coenzyme A Homeostasis

“…HoPan showed some efficacy (Task Force for Evaluation of Children's Behaviors, 1974); however, the side-effects were so severe that therapy was discontinued. The adverse side effects induced hypoglycemia, hepatic steatosis and organic acid excretion (Matsumoto et al, 1990;Matsumoto et al, 1991;Nakanishi et al, 1990;Noda et al, 1991;Ohsuga et al, 1989). We attribute these side effects to the interference of HoPan with hepatic CoA metabolism, and our findings suggest that pantothenate supplementation would overcome these side effects, as it does in our mouse model.…”

The Coenzyme A Level Modulator Hopantenate (HoPan) Inhibits Phosphopantotenoylcysteine Synthetase Activity

“…Due to its dependence on PanK for metabolic activation, and its competition with Pan for this transformation, HoPan’s effective potency is expected to be highly dependent on the amount of Pan present in the environment. Indeed, the conflicting reports on HoPan’s toxicity in various animals and humans can be reconciled with a knowledge of the circulating levels of Pan in each case, and/or whether Pan was withheld from or added to the diet. ,,, Consequently, contrary to the conclusion of some of these early studies that HoPan induces a Pan deficiency, it is more likely that an underlying Pan deficiency resulted in an apparent increase in HoPan’s potency. One could therefore reasonably conclude that HoPan may be a potent inhibitor under conditions where Pan availability is limited.…”