Ketone potentiation of haloalkane‐induced hepato‐ and nephrotoxicity. I. dose‐response relationships

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Abstract
Carbon tetrachloride (CCl4) induced hepatotoxicity and chloroform (CHCl3) induced nephrotoxicity were evaluated in male Sprague‐Dawley rats pretreated with acetone (A), methyl ethyl ketone (MEK), and methyl isobutyl ketone (MiBK). Dose‐response relationships for A, MEK, and MiBK potentiation of CCl4‐induced hepatotoxicity and CHCl3‐induced nephrotoxicity were compared. A, MEK, and MiBK pretreatment at a dosage of 6.8 mmol/kg, given daily for 3 d, markedly potentiated CCl4‐induced liver toxicity as indicated by a decrease in the CCI4 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 ranking profile for the potentiation of CCI4 hepatotoxicity of MiBK >A> MEK and of A > MEK ≥ MiBK for CHCl3 nephrotoxicity. These dissimilar ranking profiles could be due to differences in mechanisms of action for the two target sites.