The acute hepatotoxicity of the isomers of dichlorobenzene in Fischer-344 and Sprague-Dawley rats: isomer-specific and strain-specific differential toxicity.

The acute hepatotoxicity of the three isomers of dichlorobenzene (DCB) was evaluated in male Fischer-344 (F344) rats at various times following ip administration. Plasma alanine aminotransferase (ALT) activity, measured in F344 rats 24 hr postexposure, was dramatically elevated following doses of 1.8-5.4 mmol/kg of o-DCB. Conversely, equimolar doses of p-DCB produced no such toxicity, while m-DCB produced intermediate hepatic injury at or above doses of 2.7 mmol/kg. Histopathological changes in livers from treated animals qualitatively reflected elevations in 24-hr plasma ALT activity (time to maximal elevation). Phenobarbital pretreatment potentiated the acute hepatotoxicity of o- and m-DCB, but did not affect the toxicity of p-DCB. Likewise, SKF-525A pretreatment inhibited the hepatotoxicity of o-DCB. Equimolar doses of o- and m-DCB produced approximately equivalent depletion of intrahepatic glutathione, while p-DCB had no effect on hepatic GSH. Furthermore, prior depletion of hepatic glutathione by pretreatment with phorone markedly potentiated the hepatotoxicity of o- and m-DCB, while increasing the toxicity of p-DCB to a far lesser degree. The differential hepatotoxicity of the o- and m-DCB does not appear to be explained adequately by differences in their hepatic distribution or in vivo covalent binding to hepatic proteins. Interestingly, male Sprague-Dawley (SD) rats are relatively refractive to the acute hepatotoxicity of o-DCB following ip administration of 1.8 and 5.4 mmol/kg. The combination of these dramatic differences (structure-activity and animal strains) should be useful in elucidating key events involved in the hepatotoxicity caused by these compounds.

N-(2,3-dimercaptopropyl)phthalamidic acid: protection, in vivo and in vitro, against arsenic intoxication.

The ip LD50s of N-(2,3-dimercaptopropyl)phthalamidic acid (DMPA) and British Anti-Lewisite (BAL) were 0.819 and 1.48 mmol/kg, respectively, in male albino mice. The ip ED50 of DMPA and BAL for prevention of the lethal effects of 0.15 mmol NaAsO2/kg was 0.022 and 0.169 mmol/kg, respectively. DMPA increased the LD50 of sodium arsenite by approximately 2.5-fold following two ip injections of 0.20 mmol DMPA/kg. The effectiveness of DMPA in reducing the toxicity of NaAsO2 was further demonstrated by its reversal of the sodium arsenite inhibition of pyruvate dehydrogenase multienzyme complex (PDH) activity in vitro. Similarly, in an in vivo experiment in which mice received 0.10 mmol NaAsO2/kg, and 30 min later were given 0.05 or 0.10 mmol/kg DMPA, there was a rapid recovery of PDH activity. The distribution of 74As in the tissues of male New Zealand rabbits was altered following im injection of 0.20 mmol/kg DMPA. Under these conditions, the tissue concentration of 74As was significantly decreased. For all tissues tested, the 74As content decreased by at least 50% as compared to that of untreated controls. DMPA was effective also in increasing both urinary and fecal excretion of arsenic. The stability of aqueous solutions of DMPA varies with the pH of the solution. DMPA is more stable in acid solution.