Intestinal anaerobic bacteria hydrolyse sorivudine, producing the high blood concentration of 5-(E)-(2-bromovinyl)uracil that increases the level and toxicity of 5-fluorouracil

Nakayama, Haruyuki; Kinouchi, Takemi; Kataoka, Keiko; Akimoto, Shigeru; Matsuda, Yoshiko; Ohnishi, Yoshinari

doi:10.1097/00008571-199702000-00005

Cited by 109 publications

(77 citation statements)

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“…The treatment of animals with a mixture of BC, NM and SM decreased the number of both aerobes and anaerobes and yielded pseudo-germ-free animals without sophisticated germ-free isolators (16). In addition, we used KM and MNZ to decrease aerobes and anaerobes, respectively, in the intestine (26). The number of ulcers in the small intestine of rats treated with KM or a mixture (BC, NM and SM) was lower than that of the control rats (Table 5).…”

Section: Discussionmentioning

confidence: 99%

“…The rats were administered water or the antibiotics KM (250 mg/kg), MNZ (100 mg/kg) or a mixture of BC, NM and SM (200 mg/kg each) twice a day by intragastric gavage from three days before BFMeT administration until the necropsy day (16,26). Both control and antibiotic-treated rats were administered BFMeT at a dose of 1,000 mg/kg by intragastric gavage 4 hr after the antibiotic treatment.…”

Section: Methodsmentioning

confidence: 99%

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Culture Supernatants of Lactobacillus acidophilus and Bifidobacterium adolescentis Repress Ileal Ulcer Formation in Rats Treated with a Nonsteroidal Antiinflammatory Drug by Suppressing Unbalanced Growth of Aerobic Bacteria and Lipid Peroxidation

Kinouchi

Kataoka

Bing

et al. 1998

Microbiology and Immunology

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A nonsteroidal antiinflammatory drug, 5-bromo-2-(4-fluoropheny1)-3-(4-methylsulfonylphenyl) thiophene (BFMeT), induced ileal ulcers in rats after oral administration, while no ulcers were observed after subcutaneous injection. The ileal ulcer formation in BFMeT-treated rats was examined to correlate the administration of cultures of Lactobacillus acidophilus or Bifidobacterium adolescentis with intestinal bacteria in the ileal contents and lipid peroxidation of the small intestinal mucosa. Ileal ulcers were observed in more than 85% of the rats treated with BFMeT at a dose of 1,000 mg/kg when they were given tap water as drinking water. The incidence of ulcer formation was repressed by giving culture supernatants of L. acidophilus or B. adolescentis as drinking water, but not by giving the cell suspension as drinking water. Gram staining of the ileal contents of normal rats revealed that 97 % of the stained bacteria were Gram-positive rods and only 1.5% were Gram-negative rods. The percentage of Gram-negative rods 72 hr after BFMeT administration was 49.8% and increased over 30-fold in BFMeT-treated rats. However, the percentage of Gram-negative rods was 9.7% or 16%, respectively, in rats taking culture supernatants of L. acidophilus or B. adolescentis. In addition, thiobarbituric acid-reactive substances in the ileal mucosa increased significantly in the rats given tap water for 72 hr after BFMeT treatment, but not in rats given the culture supernatants of L. acidophilus or B. adolescentis. Since BFMeT induced an unbalanced intestinal microflora, the effect of antibiotic treatment on ulcer formation in rats was examined. The magnitude of the ulcer formation in the antibiotic-treated rats was, in decreasing order, metronidazole > none > kanamycin > a mixture (bacitracin, neomycin and streptomycin). These results suggest that the intestinal microflora plays an important role in ulcer formation and that a metabolite(s) of L. acidophilus and B. ado-, lescentis inhibits ileal ulcer formation by repressing changes in the intestinal microflora and lipid peroxidation in BFMeT-treated rats.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Culture Supernatants of Lactobacillus acidophilus and Bifidobacterium adolescentis Repress Ileal Ulcer Formation in Rats Treated with a Nonsteroidal Antiinflammatory Drug by Suppressing Unbalanced Growth of Aerobic Bacteria and Lipid Peroxidation

Kinouchi

Kataoka

Bing

et al. 1998

Microbiology and Immunology

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“…The combination therapy led to the toxic buildup of 5-FU due to inhibition of the 5-FU catabolic enzyme dihydropyrimidine dehydrogenase (DPD) through irreversible binding by (E)-5-(2-bromovinyl)uracil (BVU), a microbial metabolite of sorivudine (ref. 80 and Figure 3). Germfree and antibiotic-treated rats evaded the deleterious effects of combination therapy, highlighting the critical role of the gut microbiota in this fatal drug-drug interaction.…”

Section: R E V I E W S E R I E S : G U T M I C R O B I O M Ementioning

confidence: 94%

Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics

Carmody¹,

Turnbaugh²

2014

J. Clin. Invest.

212

145

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“…Increase toxicity [49,50] Zonisamide {5734} Anticonvulsant Gut microbiota is central to the metabolism of zonisamide by reduction producing 2-sulfomoyacetylphenol. Germfree rats had lower levels of this metabolite, and its levels were increased after those rats were inoculated with gut microbiota.…”

Section: Web Resources For Exploring Gut Pharmacomicrobiomicsmentioning

confidence: 99%

Diet-Microbiota Interactions and their Implications for Healthy Living

2014

Health and the Gut

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The influence of resident gut microbes on xenobiotic metabolism has been investigated at different levels throughout the past five decades. However, with the advance in sequencing and pyrotagging technologies, addressing the influence of microbes on xenobiotics had to evolve from assessing direct metabolic effects on toxins and botanicals by conventional culture-based techniques to elucidating the role of community composition on drugs metabolic profiles through DNA sequence-based phylogeny and metagenomics. Following the completion of the Human Genome Project, the rapid, substantial growth of the Human Microbiome Project (HMP) opens new horizons for studying how microbiome compositional and functional variations affect drug action, fate, and toxicity (pharmacomicrobiomics), notably in the human gut. The HMP continues to characterize the microbial communities associated with the human gut, determine whether there is a common gut microbiome profile shared among healthy humans, and investigate the effect of its alterations on health. Here, we offer a glimpse into the known effects of the gut microbiota on xenobiotic metabolism, with emphasis on cases where microbiome variations lead to different therapeutic outcomes. We discuss a few examples representing how the microbiome interacts with human metabolic enzymes in the liver and intestine. In addition, we attempt to envisage a roadmap for the future implications of the HMP on therapeutics and personalized medicine.

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Intestinal anaerobic bacteria hydrolyse sorivudine, producing the high blood concentration of 5-(E)-(2-bromovinyl)uracil that increases the level and toxicity of 5-fluorouracil

Cited by 109 publications

References 0 publications

Culture Supernatants of Lactobacillus acidophilus and Bifidobacterium adolescentis Repress Ileal Ulcer Formation in Rats Treated with a Nonsteroidal Antiinflammatory Drug by Suppressing Unbalanced Growth of Aerobic Bacteria and Lipid Peroxidation

Culture Supernatants of Lactobacillus acidophilus and Bifidobacterium adolescentis Repress Ileal Ulcer Formation in Rats Treated with a Nonsteroidal Antiinflammatory Drug by Suppressing Unbalanced Growth of Aerobic Bacteria and Lipid Peroxidation

Host-microbial interactions in the metabolism of therapeutic and diet-derived xenobiotics

Diet-Microbiota Interactions and their Implications for Healthy Living

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