KETONE POTENTIATION OF INTRAHEPATIC CHOLESTASIS - EFFECT OF 2 ALIPHATIC ISOMERS

Occupational exposure to methyl isobutyl ketone (MiBK) or methyl n-but yl ketone (MnBK) normally occurs by inhalation. The present study repo rts that exposure to both ketones can potentiate cholestasis experimen tally induced by taurolithocholic acid (TLC, 30 mu mol/kg) or by a com bination of manganese (Mn, 4.5 mg/kg) and bilirubin (BR, 25 mg/kg). Ma le Sprague-Dawley rats were exposed for 3 d, 4 h/d, to MiBK or MnBK va pors using 0.5, 1, 1.5, or 2 times the minimal effective concentration (MEC). The estimated MiBK or MnBK MEC for potentiating TLC- or Mn-BR- induced cholestasis were 400 and 150 ppm, respectively. Eighteen hours after ketone exposure, rats were injected iv with TLC or Mn-BR. Bile flow was measured from 15 to 150 min after the cholestatic regimen. Ra ts exposed to MiBK or MnBK exhibited an enhanced diminution in bile fl ow compared to controls that was dose-dependent with the inhaled keton e dose. The dose-effect characteristics of the potentiation phenomenon were established. Results indicate that MiBK or MnBK inhalation poten tiated both TLC and Mn-BR cholestasis in a dose-related fashion. Quant itative differences, however, exist between both ketones with respect to their ability to potentiate both models. Comparison between the two isomers was established, and MnBK was found to be more potent than Mi BK.