KETONE POTENTIATION OF HALOALKANE-INDUCED HEPATO-TOXICITY AND NEPHROTOXICITY .2. IMPLICATION OF MONOOXYGENASES

Previous results in Sprague-Dawley rats indicate that acetone (A), met hyl ethyl ketone (MEK) and methyl isobutyl ketone (MiBK) pretreatment (3 d, po) at dosages of 6.8 and 13.6 mmol/kg potentiate CCl4 hepatotox icity and CHCl3 nephrotoxicity, respectively. The potentiation potency profile observed was MiBK > A > MEK for liver and A > MEK greater tha n or equal to MiBK for kidney toxicity (Raymond & Plaa, 1995). In the present study, hepatic and renal microsomes from A-, MEK-, and MiBK-pr etreated rats (6.8 or 13.6 mmol/kg) were examined for cytochrome P-450 content, substrate-specific monooxygenase activity (aminopyrine and b enzphetamine N-demethylase, aniline hydroxylase) and in vitro covalent binding of (CHCl3)-C-14 and (CCl4)-C-14. Of the three ketones, only M iBK significantly increased P-450 content of liver and renal cortical microsomes. Similarly, (CCl4)-C-14 covalent binding under aerobic and anaerobic conditions was significantly increased by MiBK pretreatment only. (CHCl3)-C-14 covalent binding by renal cortical microsomes was s ignificantly increased only under aerobic conditions by MiBK pretreatm ent. MiBK (13.6 mmol/kg) increased (threefold) aminopyrine N-demethyla tion in both liver and kidney, but only benzphetamine N-demethylation (two-fold, at 6.8 and 13.6 mmol/kg) in liver; A and MEK had no effect on either monooxygenase. All ketones at dosages of 6.8 and 13.6 mmol/k g increased aniline hydroxylation in liver (twofold) and kidney (fivef old). Comparable profiles for P-450 induction, haloalkane covalent bin ding, and aminopyrine or benzphetamine N-demethylase activity were obs erved in liver and kidney microsomes. This profile was consistent with the ketone potentiation potency ranking profile observed in vivo for liver but not kidney injury. These findings affirm the importance of k etone-enhanced bioactivation for potentiation of CCl4 hepatotoxicity b ut suggest an alternative mechanism for CHCl3 nephrotoxicity.