Hepatoprotection by dimethyl sulfoxide. II. Characterization of optimal dose and the latest time of administration for effective protection against chloroform and bromobenzene induced injury

• Published in: Experimental and toxicologic pathology : official journal of the Gesellschaft für Toxikologische Pathologie Vol. 51; no. 6; pp. 537 - 543
• Main Authors: LIND, R. C, GANDOLFI, A. J
• Format: Journal Article
• Language: English
• Published: Jena Elsevier 01.11.1999
• Subjects: Animals; Biological and medical sciences; Bromobenzenes - toxicity; Chemical and Drug Induced Liver Injury; Chemical and industrial products toxicology. Toxic occupational diseases; Chloroform - toxicity; Dimethyl Sulfoxide - administration & dosage; Dimethyl Sulfoxide - pharmacology; Dose-Response Relationship, Drug; Free Radical Scavengers - administration & dosage; Free Radical Scavengers - pharmacology; Gas, fumes; Liver Diseases - prevention & control; Male; Medical sciences; Rats; Rats, Sprague-Dawley; Time Factors; Toxicology; Animal model; Chloroform; Rat; Maximal dose; Toxicity; Liver; Rodentia; Hepatic disease; Prevention; Vertebrata; Toxicology; Mammalia; Animal; Schedule; Digestive diseases
• ISSN: 0940-2993; 1618-1433
• DOI: 10.1016/S0940-2993(99)80134-1

Dimethyl sulfoxide (DMSO) has previously been shown to attenuate chloroform (CHCl3) and bromobenzene (BB) induced hepatotoxicity in the rat when a dose of 2.0 ml/kg is given 24 hr after the toxicants. However, the optimal dose of DMSO and the latest time at which DMSO can be administered and still provide effective protection have not been determined. In order to determine the latest time at which DMSO can interrupt the development of necrosis, male Sprague Dawley rats received either 0.75 ml/kg CHCl3 or 0.5 ml/kg BB, 20% in corn oil, p.o., followed by single dose of 2 ml/kg DMSO, 50% in saline, i.p., at 24, 26, 28 or 30 hr later. Positive control groups received either CHCl3 or BB and then 4.0 ml/kg saline, i.p., 24 hr later. All of the animals were then killed 48 hr after toxicant dosing. The extent of liver injury present when DMSO was administered was examined by killing animals at 24, 26, 28 or 30 hr after toxicant dosing. The optimal dose of DMSO for providing protection was estimated by administering either 0, 1.0, 2.0, 3.0 or 4.0 ml/kg DMSO at 24 hr after toxicant dosing and then killing the animals at 48 hr. Delaying DMSO administration to times later than 24 hr after toxicant dosing led to a loss of protection as indicated by both plasma ALT activity and the light microscopic appearance of liver tissue. The distinctive liver lesions present at 24 hr after CHCl3 or BB dosing rapidly expanded from being limited around central veins to bridging between centrilobular areas in only a few hours. This was accompanied by large increases in plasma ALT. With both toxicants, doses of DMSO greater than 2 ml/kg did not enhance its protective action while the lower dose of 1 ml/kg DMSO was not as effective. The loss of DMSO's antidotal action when given at times later than 24 hr after the toxicants indicates irreversible changes were underway as the centrilobular lesions progressed from being limited to more bridging in nature. Hopefully, further elucidation of the mechanism(s) by which DMSO interrupts the rapid progression of injury will both help to understand the steps involved in lesion development and provide insights into therapeutic interventions for drug and chemical induced hepatitis.