Ketone potentiation of intrahepatic cholestasis: effect of two aliphatic isomers

Occupational exposure to methyl isobutyl ketone (MiBK) or methyl n-butyl ketone (MnBK) normally occurs by inhalation. The present study reports that exposure to both ketones can potentiate cholestasis experimentally induced by taurolithocholic acid (TLC, 30 mumol/kg) or by a combination of manganese (Mn, 4.5 mg/kg) and bilirubin (BR, 25 mg/kg). Male Sprague-Dawley rats were exposed for 3 d, 4 h/d, to MiBK or MnBK vapors 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 i.v. with TLC or Mn-BR. Bile flow was measured from 15 to 150 min after the cholestatic regimen. Rats exposed to MiBK or MnBK exhibited an enhanced diminution in bile flow compared to controls that was dose-dependent with the inhaled ketone dose. The dose-effect characteristics of the potentiation phenomenon were established. Results indicate that MiBK or MnBK inhalation potentiated both TLC and Mn-BR cholestasis in a dose-related fashion. Quantitative 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 MiBK.