Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11)

Chen, Shujuan; Yueh, Mei‐Fei; Bigo, Cyril; Barbier, Olivier; Wang, Kepeng; Karin, Michael; Nguyen, Nghia; Tukey, Robert H.

doi:10.1073/pnas.1319123110

Cited by 97 publications

(81 citation statements)

References 41 publications

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“…5). SN-38 significantly shortened the length of villi at 2 days after termination of 5-day continuous administration, which is in accordance with previous observations after administration of CPT-11 (Chen et al, 2013). Interestingly, apple juice was able to protect intestinal tissues from SN-38-induced gastrointestinal toxicity, presumably owing to decreased intestinal uptake of SN-38.…”

Section: Discussionsupporting

confidence: 91%

Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride

Fujita

Saito

Nakanishi

et al. 2015

Drug Metabolism and Disposition

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Gastrointestinal toxicity, such as late-onset diarrhea, is a significant concern in irinotecan hydrochloride (CPT-11)-containing regimens. Prophylaxis of late-onset diarrhea has been reported with use of Japanese traditional (Kampo) medicine containing baicalin and with the antibiotic cefixime, and this has been explained in terms of inhibition of bacterial deconjugation of SN-38-glucuronide since unconjugated SN-38 (active metabolite of CPT-11) is responsible for the gastrointestinal toxicity. It is also prerequisite for SN-38 to be accumulated in intestinal tissues to exert toxicity. Based on the fact that liver-specific organic anion transporting polypeptide (OATP) 1B1, a member of the same family as OATP2B1, is known to be involved in hepatic transport of SN-38, we hypothesized that intestinal transporter OATP2B1 contributes to the accumulation of SN-38 in gastrointestinal tissues, and its inhibition would help prevent associated toxicity. We found that uptake of SN-38 by OATP2B1-expressing Xenopus oocytes was significantly higher than that by control oocytes. OATP2B1-mediated uptake of SN-38 was saturable, pH dependent, and decreased in the presence of baicalin, cefixime, or fruit juices such as apple juice. In vivo gastrointestinal toxicity of SN-38 in mice caused by oral administration for consecutive 5 days was prevented by coingestion of apple juice. Thus, OATP2B1 contributes to the uptake of SN-38 by intestinal tissues, triggering gastrointestinal toxicity. So, in addition to the reported inhibition of bacterial b-glucuronidase by cefixime or baicalin, inhibition of OATP2B1 may also contribute to prevention of gastrointestinal toxicity. Apple juice may be helpful for prophylaxis of late-onset diarrhea observed in CPT-11 therapy without disturbance of the intestinal microflora.

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Section: Discussionsupporting

confidence: 91%

Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride

Fujita

Saito

Nakanishi

et al. 2015

Drug Metabolism and Disposition

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“…Liver and small intestinal microsomes from mice were prepared as previously described (Chen et al, 2013). All Western blots were performed by using NuPAGE 4-12% BisTrispolyacrylamide gels as outlined by the supplier (Invitrogen/ ThermoFisher Scientific, Waltham, MA).…”

Section: Methodsmentioning

confidence: 99%

“…Membranes were washed and incubated with horseradish peroxidase-conjugated secondary antibody for 1 hour. Antibodies used were a rabbit anti-human UGT1A1 (Chen et al, 2013) and a mouse anti-bovine myelin basic protein (Bio-Rad, Hercules, CA). Both antibodies crossreacted with the mouse proteins.…”

Section: Methodsmentioning

confidence: 99%

“…Bilirubin glucuronidation activity assay was performed as described previously (Chen et al, 2013). In brief, mouse liver microsomes or small intestinal microsomes were incubated with different concentrations of bilirubin in reaction buffer containing 2 mM UDP-glucuronic acid.…”

Section: Methodsmentioning

confidence: 99%

“…Mouse tissues were collected and snap-frozen into liquid nitrogen, and then pulverized. Aliquots of the pulverized samples were homogenized in TRIzol (Invitrogen) for RNA isolation (Chen et al, 2013). Reverse transcription (RT) was conducted by using iScript Reverse Transcriptase (BioRad) as outlined by the manufacturer.…”

Section: Methodsmentioning

confidence: 99%

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Reduced Myelination and Increased Glia Reactivity Resulting from Severe Neonatal Hyperbilirubinemia

et al. 2015

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Bilirubin-induced neurologic dysfunction (BIND) and kernicterus has been used to describe moderate to severe neurologic dysfunction observed in children exposed to excessive levels of total serum bilirubin (TSB) during the neonatal period. Here we use a new mouse model that targets deletion of the Ugt1 locus and the Ugt1a1 gene in liver to promote hyperbilirubinemiainduced seizures and central nervous system toxicity. The accumulation of TSB in these mice leads to diffuse yellow coloration of brain tissue and a marked cerebellar hypoplasia that we characterize as kernicterus. Histologic studies of brain tissue demonstrate that the onset of severe neonatal hyperbilirubinemia, characterized by seizures, leads to alterations in myelination and glia reactivity. Kernicterus presents as axonopathy with myelination deficits at different brain regions, including pons, medulla oblongata, and cerebellum. The excessive accumulation of TSB in the early neonatal period (5 days after birth) promotes activation of the myelin basic protein (Mbp) gene with an accelerated loss of MBP that correlates with a lack of myelin sheath formation. These changes were accompanied by increased astroglial and microglial reactivity, possibly as a response to myelination injury. Interestingly, cerebellum was the area most affected, with greater myelination impairment and glia burden, and showing a marked loss of Purkinje cells and reduced arborization of the remaining ones. Thus, kernicterus in this model displays not only axonal damage but also myelination deficits and glial activation in different brain regions that are usually related to the neurologic sequelae observed after severe hyperbilirubinemia.

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The Interplay Between Drug Release and Intestinal Gut‐Wall Metabolism

Darwich¹,

Hatley²,

Olivares‐Morales³

et al. 2022

Oral Drug Delivery for Modified Release Formulations

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Intestinal glucuronidation protects against chemotherapy-induced toxicity by irinotecan (CPT-11)

Cited by 97 publications

References 41 publications

Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride

Organic Anion Transporting Polypeptide (OATP)2B1 Contributes to Gastrointestinal Toxicity of Anticancer Drug SN-38, Active Metabolite of Irinotecan Hydrochloride

Reduced Myelination and Increased Glia Reactivity Resulting from Severe Neonatal Hyperbilirubinemia

The Interplay Between Drug Release and Intestinal Gut‐Wall Metabolism

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