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.

Ethanol oxidation and acetaldehyde production in vitro by human intestinal strains of Escherichia coli under aerobic, microaerobic, and anaerobic conditions.

BACKGROUND: Many human colonic facultative anaerobic and aerobic bacteria are capable of alcohol dehydrogenase (ADH)-mediated ethanol oxidation. In this bacteriocolonic pathway for ethanol oxidation intracolonic ethanol is first oxidized by bacterial ADHs to acetaldehyde, which is further oxidized by either colonic mucosal or bacterial aldehyde dehydrogenases to acetate. The produced acetaldehyde is a highly toxic and carcinogenic agent. This study was aimed to investigate the ethanol oxidation capability and acetaldehyde formation of Escherichia coli IH 50546 and IH 50817. These intestinal E. coli strains expressed either high (IH 50546) or low (IH 50817) ADH activity. METHODS: Strains were cultured for 48 h on agar plates supplemented with ethanol under aerobic, microaerobic (6% O2), and anaerobic conditions. RESULTS: Under aerobic conditions both E. coli strains oxidized ethanol. The ethanol consumption rates (ECR) were 1.046+/-0.025 mM/h and 0.367+/-0.148 mM/h with IH 50546 and IH 50817, respectively. In the case of IH 50546 this was associated with significant acetaldehyde production (418+/-13 microM), suggesting ADH-mediated ethanol oxidation. Under microaerobic conditions only IH 50546 was able to oxidize ethanol (ECR, 0.498+/-0.074 mM/h) and to produce acetaldehyde (up to 440+/-76 microM) to significant extents. Under anaerobic conditions both strains fermented glucose to ethanol. CONCLUSIONS: This study experimentally shows the potential of certain bacteria representing normal human colonic flora to produce acetaldehyde under various atmospheric conditions that may prevail in different parts of the GI tract. This bacterial adaptation may be an essential feature of the bacteriocolonic pathway to produce toxic and carcinogenic acetaldehyde from either endogenous or exogenous ethanol.