The impact of intestinal microflora on serum bilirubin levels

Vı́tek, Libor; Zelenka, Jaroslav; Zadinová, M; Malina, Jiří

doi:10.1016/j.jhep.2004.10.012

Cited by 59 publications

(53 citation statements)

References 28 publications

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“…Additionally, for patients with colorectal cancer, the use of antibiotics to treat CPT-11-induced toxicity may lead to the increased prevalence of subdominant bacterial species with higher overall b-glucuronidase activity in the GI tract and thus, increased toxicity (Brandi et al, 2006). Studies have also shown that the long-term use of neomycin in mice leads to increased serum bilirubin that may interfere with proper hepatic CPT-11 metabolism (Vítek et al, 2005). These observations lead to the conclusion that the selective, nonlethal inhibition of components of the GI microbiome will be an important method of enhancing drug efficacy and tolerance.…”

Section: Discussionmentioning

confidence: 99%

Molecular Insights into Microbialβ-Glucuronidase Inhibition to Abrogate CPT-11 Toxicity

et al. 2013

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Bacterial b-glucuronidases expressed by the symbiotic intestinal microbiota appear to play important roles in druginduced epithelial cell toxicity in the gastrointestinal (GI) tract. For the anticancer drug CPT-11 (irinotecan) and the nonsteroidal anti-inflammatory drug diclofenac, it has been shown that removal of the glucuronide moieties from drug metabolites by bacterial b-glucuronidases in the GI lumen can significantly damage the intestinal epithelium. Furthermore, selective disruption of bacterial b-glucuronidases by small molecule inhibitors alleviates these side effects, which, for CPT-11 {7-ethyl-10-[4-(1-piperidino)-1-piperidino]}, can be dose limiting. Here we characterize novel microbial b-glucuronidase inhibitors that inhibit Escherichia coli b-glucuronidase in vitro with K i values between 180 nM and 2 mM, and disrupt the enzyme in E. coli cells, with EC 50 values as low as 300 nM. All compounds are selective for E. coli b-glucuronidase without inhibiting purified mammalian b-glucuronidase, and they do not impact the survival of either bacterial or mammalian cells. The 2.8 Å resolution crystal structure of one inhibitor bound to E. coli b-glucuronidase demonstrates that it contacts and orders only a portion of the "bacterial loop" present in microbial, but not mammalian, b-glucuronidases. The most potent compound examined in this group was found to protect mice against CPT-11-induced diarrhea. Taken together, these data advance our understanding of the chemical and structural basis of selective microbial b-glucuronidase inhibition, which may improve human drug efficacy and toxicity.

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Section: Discussionmentioning

confidence: 99%

Molecular Insights into Microbialβ-Glucuronidase Inhibition to Abrogate CPT-11 Toxicity

et al. 2013

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“…In fact, the suppression of some dominant bacterial populations may allow the overgrowth of smaller populations [e.g., increasing the overall h-glucuronidase activity (carried for a subdominant bacterial species)]. Furthermore, there is recent evidence that the long-term use of neomycin in rodents increases serum bilirubin, thus potentially interfering with hepatic irinotecan metabolism (43). At present, the safest way to decrease irinotecan delayed diarrhea seems to be the oral alkalinization of the intestinal lumen because a higher pH reduces the deconjugation of SN-38 glucuronide (37).…”

Section: Discussionmentioning

confidence: 99%

Intestinal microflora and digestive toxicity of irinotecan in mice.

Brandi

Dabard

Raibaud

et al. 2006

Clinical Cancer Research

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Purpose: Delayed diarrhea is the most important side effect of irinotecan. The aim of this study was to investigate the role of intestinal microflora on the induction of systemic and intestinal toxicity and diarrhea, studying germ-free and holoxenic mice i.p. injected with irinotecan. Experimental Design: To evaluate the lethal dose, starting with 100 mg/kg/4 d, we treated the holoxenic mice with100, 80, and 60 mg/kg/4 d and germ-free mice with 60, 80,100, and150 mg/ kg/4 d. We recorded the percentage of dead animals, diarrhea, and the epithelial damage to the jejunum, ileum, cecum, and colon at optical and scanning electron microscopy. Results: Germ-free mice were more resistant to irinotecan than the holoxenic group. The lethal dose was between 60 and 80 mg of irinotecan for holoxenic mice and z150 mg for the germ-free. The intestinal damage score was higher in holoxenic than germ-free mice at 100 mg and equally diffuse in the small and large bowel. The damage in germ-free mice was less severe (8 of 40 samples) prevailing in the ileum. The differences were significant for all sites (jejunum, P < 0.001; ileum, P = 0.012; cecum, P = 0.001; colon, P < 0.001). No damage was found in germ-free mice at 60 mg. Diarrhea was present in all 100 and 80 mg holoxenic mice and in 19 of 20 cases at 60 mg whereas it was absent in 60 mg or sporadic in 80 and 100 mg germ-free mice. Conclusions: The intestinal microflora plays a key role in the intestinal toxicity of irinotecan.

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“…30 Similar biliary excretion rates of bile salts between controls and Orl-treated Gunn rats are not compatible with major differences in the intestinal concentration of bile salts. Vitek et al 44 recently showed that the intestinal microflora can substantially affect the metabolism of bilirubin. Effects of Orl on the composition of the intestinal microflora or on intestinal bilirubin metabolizing activity are not known.…”

Section: Discussionmentioning

confidence: 99%

Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats†

et al. 2005

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We sought to develop an oral treatment for unconjugated hyperbilirubinemia. In the Gunn rat model of unconjugated hyperbilirubinemia, dietary supplementation with the lipase inhibitor orlistat (Orl) or with calcium phosphate (CaP) decreases plasma unconjugated bilirubin (UCB) levels. We determined whether Orl, CaP, or their combination is superior to phototherapy, the conventional treatment, and whether the effects of Orl and CaP are influenced by dietary fat content. Gunn rats were treated with Orl (200 mg/kg chow), CaP (20 g/kg chow), Orl ؉ CaP, or continuous phototherapy (19 W/cm 2 /nm) during a low-fat (LF) diet (13 energy%) or high-fat (HF) diet (35 energy%). Plasma UCB and fecal fat excretion were measured before, during, and/or at the end of treatment. Orl treatment for 2 weeks (HF diet) reduced plasma UCB concentrations similar to phototherapy (؊34% and ؊28%, respectively); the combination of both was more effective than either treatment alone (؊48%; P < .001). After 3 weeks of a HF diet, plasma UCB was 46% lower compared with the LF diet (P < .001). Plasma UCB concentrations were negatively correlated with fecal fat excretion (r ‫؍‬ ؊0.96; P < .001). Irrespective of dietary fat content, 3 weeks of combined treatment (Orl ؉ CaP) decreased plasma UCB by approximately 50% (P < .01) and was more effective than phototherapy (P < .05) at the intensity provided. C rigler-Najjar disease is characterized by a permanent unconjugated hyperbilirubinemia due to absent (type I) or decreased (type II) activity of the hepatic enzyme bilirubin-UDP-glucuronosyltransferase. 1 Severe unconjugated hyperbilirubinemia can lead to bilirubin encephalopathy, kernicterus, and death. 2,3 Phenobarbital treatment can usually control unconjugated hyperbilirubinemia in Crigler-Najjar type II patients via residual enzyme induction. 4,5 Phenobarbital is not effective in Crigler-Najjar disease type I, however, so these patients have to undergo daily phototherapy, which has considerable disadvantages. Phototherapy becomes less effective with age, probably due to skin alterations, 6,7 a decrease in the surface area to body mass ratio, 8 and a diminishing compliance to the intensive phototherapy regimen, which may take up to 12 hours per day. 6 To prevent irreversible brain damage due to kernicterus, many patients with CriglerNajjar disease type I undergo liver transplantation in their second decade. 9,10 We sought to develop an alternative treatment for unconjugated hyperbilirubinemia based on oral administration and with equal or higher efficacy than phototherapy. The oral treatment strategy used in the present study is based on reducing the reabsorption of UCB 11,12 through intestinal capture. Reabsorption of UCB can contribute substantially to the pathogenesis

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The impact of intestinal microflora on serum bilirubin levels

Cited by 59 publications

References 28 publications

Molecular Insights into Microbialβ-Glucuronidase Inhibition to Abrogate CPT-11 Toxicity

Molecular Insights into Microbialβ-Glucuronidase Inhibition to Abrogate CPT-11 Toxicity

Intestinal microflora and digestive toxicity of irinotecan in mice.

Effective oral treatment of unconjugated hyperbilirubinemia in Gunn rats†

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