Metronidazole increases intracolonic but not peripheral blood acetaldehyde in chronic ethanol-treated rats.
BACKGROUND
Metronidazole leads to the overgrowth of aerobic flora in the large intestine by reducing the number of anaerobes. According to our previous studies, this shift may increase intracolonic bacterial acetaldehyde formation if ethanol is present. Metronidazole is also reported to cause disulfiram-like effects after alcohol intake, although the mechanism behind this is obscure. Therefore, the aim was to study the effect of long-term metronidazole and alcohol treatment on intracolonic acetaldehyde levels and to explore the possible role of intestinal bacteria in the metronidazole related disulfiram-like reaction.


METHODS
A total of 32 rats were divided into four groups: controls (n = 6), controls receiving metronidazole (n = 6), ethanol group (n = 10), and ethanol and metronidazole group (n = 10). All rats were pair-fed with the liquid diet for 6-weeks, whereafter blood and intracolonic acetaldehyde levels and liver and colonic mucosal alcohol (ADH) and aldehyde dehydrogenase (ALDH) activities were analyzed.


RESULTS
The rats receiving ethanol and metronidazole had five times higher intracolonic acetaldehyde levels than the rats receiving only ethanol (431.4 +/- 163.5 microM vs. 84.7 +/- 14.4 microM,p = 0.0035). In contrast, blood acetaldehyde levels were equal. Cecal cultures showed the increased growth of Enterobacteriaceae in the metronidazole groups. Metronidazole had no inhibitory effect on hepatic or colonic mucosal ADH and ALDH activities.


CONCLUSIONS
The increase in intracolonic acetaldehyde after metronidazole treatment is probably due to the replacement of intestinal anaerobes by ADH-containing aerobes. Unlike disulfiram, metronidazole neither inhibits liver ALDH nor increases blood acetaldehyde. Thus, our findings suggested that the mechanism behind metronidazole related disulfiram-like reaction might be located in the gut flora instead of the liver.
Tillonen
J
J
Research Unit of Alcohol Diseases, Helsinki University Central Hospital, Finland.
Väkeväinen
S
S
Salaspuro
V
V
Zhang
Y
Y
Rautio
M
M
Jousimies-Somer
H
H
Lindros
K
K
Salaspuro
M
M
D000079:Acetaldehyde / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008795:Metronidazole / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000900:Anti-Bacterial Agents; D002492:Central Nervous System Depressants; D008795:Metronidazole; D000431:Ethanol; D000079:Acetaldehyde