Methoxyflurane enhances allyl alcohol hepatotoxicity in rats. Possible involvement of increased acrolein formation.
The effect of methoxyflurane anesthesia on allyl alcohol-induced hepatotoxicity and the metabolism of allyl alcohol was studied in male rats. Hepatotoxicity was assessed by the measurement of serum alanine aminotransferase activity and histopathological examination. Allyl alcohol-induced hepatotoxicity was enhanced when allyl alcohol (32 mg/kg) was administered 4 hr before or up to 8 days after a single 10-min exposure to methoxyflurane vapors. The possibility that methoxyflurane increases alcohol dehydrogenase-dependent oxidation of allyl alcohol to acrolein, the proposed toxic metabolite, was evaluated by measuring the rate of acrolein formation in the presence of allyl alcohol and liver cytosol. The effect of methoxyflurane on alcohol dehydrogenase activity in liver cytosol was also assessed by measuring the rate of NAD+ utilization in the presence of ethyl alcohol or allyl alcohol. Alcohol dehydrogenase activity and rate of acrolein formation were elevated in methoxyflurane-pretreated rats. The results suggest that a modest increase in alcohol dehydrogenase activity and rate of acrolein formation markedly enhances allyl alcohol-induced hepatotoxicity.
Kershaw
W C
WC
Department of Pharmacology and Toxicology, Philadelphia College of Pharmacy, PA.
Barsotti
D A
DA
Leonard
T B
TB
Dent
J G
JG
Lage
G L
GL
D000433:1-Propanol / Q000097:blood / Q000633:toxicity; D000171:Acrolein / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D003600:Cytosol / Q000032:analysis; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008733:Methoxyflurane / Q000097:blood / Q000494:pharmacology*; D020005:Propanols; D011485:Protein Binding; D051381:Rats; D013997:Time Factors
D000447:Aldehydes; D020005:Propanols; D008733:Methoxyflurane; C006463:allyl alcohol; D000171:Acrolein; D000433:1-Propanol; D000429:Alcohol Oxidoreductases