KETONE POTENTIATION OF HALOALKANE-INDUCED HEPATOTOXICITY AND NEPHROTOXICITY .1. DOSE-RESPONSE RELATIONSHIPS

Carbon tetrachloride (CCl4) induced hepatotoxicity and chloroform (CHC l3) induced nephrotoxicity were evaluated in male Sprague-Dawley rats pretreated with acetone (A), methyl ethyl ketone (MEK), and methyl iso butyl ketone (MiBK). Dose-response relationships for A, MEK, and MiBK potentiation of CCl4-induced hepatotoxicity and CHCl3- induced nephrot oxicity were compared. A, MEK, and MiBK pretreatment at a dosage of 6. 8 mmol/kg, given daily for 3 d, markedly potentiated CCl4-induced live r toxicity as indi- cated by a decrease in the CCl4 ED50 to 3.4, 4.6, and 1.8 mmol/kg, respectively, compared to vehicle-pretreated rats (17 .1 mmol/kg). Similarly, pretreatment with these ketones (13.6 mmol/kg) potentiated CHCl3 kidney toxicity but to a lesser degree; CHCl3 ED50 values for vehicle-, A-, MEK-, and MiBK-pretreated rats were 3.4, 1.6, 2.1, and 2.2 mmol/kg, respectively. Our results indicate a potency ra nking profile for the potentiation of CCl4 hepatotoxicity of MiBK > A > MEK and of A > MEK greater than or equal to MiBK for CHCl3 nephrotox icity. These dissimilar ranking profiles could be due to differences i n mechanisms of action for the two target sites.