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Effects of beta-lactam antibiotics on the acetaldehyde-metabolizing system in germ-free rats
T Matsubara1, S Otsubo, A Ogawa
1Shionogi Research Laboratories, Shionogi & Co. Ltd., Osaka, Japan.
Abstract:
Effects of several beta-lactam antibiotics on the acetaldehyde-metabolizing system were studied using germ-free rats. Administration of cefamandole (CMD) to the rats caused a decrease in liver mitochondrial low Km aldehyde dehydrogenase activity and an increase in blood acetaldehyde level during ethanol metabolism, similar to the case in conventional rats. Oral administration of CMD produced a pronounced increase in blood acetaldehyde level compared to the subcutaneous administration of the antibiotic. When the animals were given various beta-lactam antibiotics subcutaneously, only the antibiotics having an N-methyltetrazolylthiomethyl group at the 3-position of the cephalosporin nucleus exhibited the disulfiram-like effects on the acetaldehyde-metabolizing system. The results indicate that intestinal bacteria do no participate in the development of the disulfiram-like reaction of several beta-lactam antibiotics.
Insights
Certain beta-lactam antibiotics, like cefamandole (CMD), disrupt acetaldehyde metabolism by reducing aldehyde dehydrogenase activity. This effect, causing increased blood acetaldehyde, occurs independently of intestinal bacteria.
Area of Science:
- Pharmacology
- Biochemistry
- Toxicology
Background:
- Beta-lactam antibiotics are widely used.
- Some beta-lactams are known to cause disulfiram-like reactions.
- The role of intestinal bacteria in these reactions is not fully understood.
Purpose of the Study:
- To investigate the effects of beta-lactam antibiotics on the acetaldehyde-metabolizing system.
- To determine if intestinal bacteria are involved in the disulfiram-like effects of beta-lactam antibiotics.
Main Methods:
- Studies were conducted using germ-free rats to eliminate the influence of intestinal bacteria.
- Cefamandole (CMD) was administered to assess its impact on liver mitochondrial low Km aldehyde dehydrogenase activity and blood acetaldehyde levels during ethanol metabolism.
- Various beta-lactam antibiotics with specific structural features were administered subcutaneously.
Main Results:
- Cefamandole administration decreased liver mitochondrial low Km aldehyde dehydrogenase activity and increased blood acetaldehyde levels.
- Oral CMD administration resulted in a more pronounced increase in blood acetaldehyde compared to subcutaneous administration.
- Only beta-lactam antibiotics with an N-methyltetrazolylthiomethyl group at the 3-position of the cephalosporin nucleus showed disulfiram-like effects.
Conclusions:
- Intestinal bacteria do not play a role in the development of disulfiram-like reactions caused by several beta-lactam antibiotics.
- The disulfiram-like effects are linked to specific chemical structures within the beta-lactam molecule, particularly the N-methyltetrazolylthiomethyl group.