The objective of this proposal is to determine the mechanism of the late protective effect of dimethylsulfoxide (DMSO) against hepatotoxicants. In preliminary studies, DMSO has been shown to reverse the hepatotoxicity produced by halothane, bromobenzene, and chloroform when administered up to 24 hr after the toxicant exposure. While DMSO has a myriad of pharmacological and physiological actions, it is only approved for treatment of interstitial cystitis. The mechanism of its remarkable reversal of the hepatotoxic effects produced by these toxicants remains unknown. The first studies will characterize the optimum DMSO dose and time for administration (Aim 1). To demonstrate the universality of DMSO as a late protective agent, 4 toxicants (halothane, chloroform, bromobenzene, and vinylidene chloride), which produce different types of reactive intermediates with different initial sites of toxicity, will be studied using two species (rat and guinea pig). Two of these animal models will be used to examine if DMSO's protections results from late alterations in the biotransformation/ bioactivation of the hepatotoxicants (Aim 2). Based on the known effects of DMSO and the results of Aims 1 and 2, a single hepatotoxicant/DMSO model in the rat will be selected and used to examine if DMSO protects by altering the response of Kupffer cells or infiltrating inflammatory cells (Aim 3). Using this same model, investigations will be performed to determine if the late protective effects of DMSO results from facilitating hepatic microcirculation (Aim 5). Hepatotoxicant-exposed individuals are usually seen clinically after the hepatotoxicant-induced liver injury is well underway. Logical attempts at therapy have not been effective and intensive support with hope of hepatocyte regeneration has been the treatment. DMSO offers a unique therapy that can be given even a day after the insult and holds great promise.
| Begay, Carmen K; Gandolfi, A Jay (2003) Late administration of COX-2 inhibitors minimize hepatic necrosis in chloroform induced liver injury. Toxicology 185:79-87 |
| Lind, R C; Begay, C K; Gandolfi, A J (2000) Hepatoprotection by dimethyl sulfoxide. III. Role of inhibition of the bioactivation and covalent bonding of chloroform. Toxicol Appl Pharmacol 166:145-50 |
| Lind, R C; Gandolfi, A J (1999) Hepatoprotection by dimethyl sulfoxide. I. Protection when given twenty-four hours after chloroform or bromobenzene. Toxicol Pathol 27:342-7 |
| Lind, R C; Gandolfi, A J (1999) Hepatoprotection by dimethyl sulfoxide. II. Characterization of optimal dose and the latest time of administration for effective protection against chloroform and bromobenzene induced injury. Exp Toxicol Pathol 51:537-43 |
