An epoxysuccinic acid derivative(loxistatin)-induced hepatic injury in rats and hamsters

Journal Article · Wed Aug 01 00:00:00 EDT 1990 · Toxicology and Applied Pharmacology; (USA)

DOI:https://doi.org/10.1016/0041-008X(90)90353-V· OSTI ID:6420380

Fukushima, K; Arai, M; Kohno, Y; Suwa, T; Satoh, T ^[1]

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1. Research Center, Taisho Pharmaceutical Co., Ltd., Saitama (Japan)

Loxistatin is a possible therapeutic agent of muscular dystrophy. A single oral administration of loxistatin to male rats caused focal necrosis of the liver with inflammatory cell infiltration. The severity of the lesions was dose-dependent up to 200 mg/kg and also manifest by an increase in serum alanine aminotransferase and aspartate aminotransferase activities. Hepatic glutathione (GSH) levels decreased with a maximum 20% depletion within 5 hr after the oral administration of loxistatin. Pretreatment with diethyl maleate did not potentiate the loxistatin-induced hepatic injury. On the other hand, the hepatoprotective effect of cysteamine was observed when cysteamine was administered 24 hr before loxistatin dosing, but the effect was not observed when the antidote was administered concomitantly with loxistatin. Pretreatment of rats with phenobarbital or trans-stilbene oxide provided partial protection against the hepatotoxic effect of loxistatin. Pretreatment with SKF-525A resulted in increased hepatic injury, while pretreatment with piperonyl butoxide, cimetidine, or 3-methylcholanthrene had no effect on hepatic damage by loxistatin. Five hours after (14C)loxistatin administration to rats, the covalent binding of the radioactivity to proteins was greatest in the liver, followed by the kidney, then muscle and blood to a lesser extent. (14C)Loxistatin acid, the pharmacologically active form of loxistatin, irreversibly bound to rat liver microsomal proteins; more binding occurred when the NADPH-generating system was omitted and when the microsomes were boiled first. GSH did not alter the extent of irreversible binding, whereas N-ethylmaleimide decreased the binding of (14C)loxistatin acid to rat liver microsomal proteins by 75%. Unlike the rat, administration of loxistatin to hamsters caused neither hepatic injury nor hepatic GSH depletion.

• OSTI ID: 6420380
• Journal Information: Toxicology and Applied Pharmacology; (USA), Journal Name: Toxicology and Applied Pharmacology; (USA) Vol. 105:1; ISSN TXAPA; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

550901* -- Pathology-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINES
AMINO ACIDS
AMINOTRANSFERASES
ANIMALS
BODY
CARBON 14 COMPOUNDS
CARBOXYLIC ACIDS
DIGESTIVE SYSTEM
DIGESTIVE SYSTEM DISEASES
DISEASES
DISTRIBUTION
DOSE-RESPONSE RELATIONSHIPS
DRUGS
ENZYME ACTIVITY
ENZYME INHIBITORS
ENZYMES
GLANDS
GLUTATHIONE
HAMSTERS
IN VITRO
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
LEUCINE
LIVER
MAMMALS
MEA
NITROGEN TRANSFERASES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
PATHOGENESIS
PATHOLOGICAL CHANGES
PEPTIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RATS
RODENTS
THIOLS
TISSUE DISTRIBUTION
TOXICITY
TRACER TECHNIQUES
TRANSFERASES
VERTEBRATES