Gut microbiome affects the metabolism of metronidazole in mice through regulation of hepatic cytochromes P450 expression

Zemanová, Nina; Lněničková, Kateřina; Vavrečková, Markéta; Anzenbacherová, Eva; Anzenbacher, Pavel; Zapletalová, Iveta; Hermanová, Petra; Hudcovic, Tomáš; Kozáková, Hana; Jourová, Lenka

doi:10.1371/journal.pone.0259643

Cited by 9 publications

(3 citation statements)

References 36 publications

(49 reference statements)

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“…Metronidazole is considered to have broad toxicological prospects compared to most xenobiotics due to its biotransformation in the liver through oxidation, hydroxylation, and conjugation of metronidazole glucuronide [17]. Moreover, a cumulative number of studies on animals and humans indicated an association of metronidazole with the disturbance of alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), alkaline phosphatase (ALP), total cholesterol (TC), and triglyceride (TG), which are factors involved in hepatotoxicity [18].…”

Section: Introductionmentioning

confidence: 99%

Exploration of Maternal and Fetal Toxicity Risks for Metronidazole-Related Teratogenicity and Hepatotoxicity through an Assessment in Albino Rats

AbdRabou

Alrashdi

Alruwaili

et al. 2023

Toxics

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Metronidazole is the primary antimicrobial drug for treating acute and chronic vaginal pathogens during pregnancy; however, there has been insufficient research on placental disorders, early pregnancy loss, and preterm birth. Here, the potential activity of metronidazole on pregnancy outcomes was investigated. 130 mg/kg body weight of metronidazole was orally given individually to pregnant rats on gestation days 0–7, 7–14, and 0–20. Pregnancy outcome evaluations were carried out on gestation day 20. It was demonstrated that metronidazole could induce maternal and fetal hepatotoxicity. There is a significant increase in the activities of maternal hepatic enzymes (ALT, AST, and ALP), total cholesterol, and triglycerides compared with the control. These biochemical findings were evidenced by maternal and fetal liver histopathological alterations. Furthermore, metronidazole caused a significant decrease in the number of implantation sites and fetal viability, whereas it caused an increase in fetal lethality and the number of fetal resorptions. In addition, a significant decrease in fetal weight, placental weight, and placental diameter was estimated. Macroscopical examination revealed placental discoloration and hypotrophy in the labyrinth zone and the degeneration of the basal zone. The fetal defects are related to exencephaly, visceral hernias, and tail defects. These findings suggest that the administration of metroniazole during gestation interferes with embryonic implantation and fetal organogenesis and enhances placental pathology. We can also conclude that metronidazole has potential maternal and fetal risks and is unsafe during pregnancy. Additionally, it should be strictly advised and prescribed, and further consideration should be given to the associated health risks.

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Section: Introductionmentioning

confidence: 99%

Exploration of Maternal and Fetal Toxicity Risks for Metronidazole-Related Teratogenicity and Hepatotoxicity through an Assessment in Albino Rats

AbdRabou

Alrashdi

Alruwaili

et al. 2023

Toxics

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“…Gut microbiota is not only an important agent during pathophysiological processes but it can also influence pharmacotherapy outcomes by affecting the biotransformation and pharmacokinetics of a wide range of clinically used drugs including the drugs used to treat IBD ( Jourova et al, 2016 ; Jourova et al, 2019 ; Zemanová et al, 2021 ). Moreover, the gut microbiome may also indirectly influence the level of drug-metabolizing enzymes through bacterial metabolites.…”

Section: Introductionmentioning

confidence: 99%

Butyrate Treatment of DSS-Induced Ulcerative Colitis Affects the Hepatic Drug Metabolism in Mice

et al. 2022

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The development of inflammatory bowel disease (IBD) is associated with alterations in the gut microbiota. There is currently no universal treatment for this disease, thus emphasizing the importance of developing innovative therapeutic approaches. Gut microbiome-derived metabolite butyrate with its well-known anti-inflammatory effect in the gut is a promising candidate. Due to increased intestinal permeability during IBD, butyrate may also reach the liver and influence liver physiology, including hepatic drug metabolism. To get an insight into this reason, the aim of this study was set to clarify not only the protective effects of the sodium butyrate (SB) administration on colonic inflammation but also the effects of SB on hepatic drug metabolism in experimental colitis induced by dextran sodium sulfate (DSS) in mice. It has been shown here that the butyrate pre-treatment can alleviate gut inflammation and reduce the leakiness of colonic epithelium by restoration of the assembly of tight-junction protein Zonula occludens-1 (ZO-1) in mice with DSS-induced colitis. In this article, butyrate along with inflammation has also been shown to affect the expression and enzyme activity of selected cytochromes P450 (CYPs) in the liver of mice. In this respect, CYP3A enzymes may be very sensitive to gut microbiome-targeted interventions, as significant changes in CYP3A expression and activity in response to DSS-induced colitis and/or butyrate treatment have also been observed. With regard to medications used in IBD and microbiota-targeted therapeutic approaches, it is important to deepen our knowledge of the effect of gut inflammation, and therapeutic interventions were followed concerning the ability of the organism to metabolize drugs. This gut–liver axis, mediated through inflammation as well as microbiome-derived metabolites, may affect the response to IBD therapy.

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“…Accumulating evidence shows that gut microbiota has a certain capacity of drug biotransformation with various consequences on the drug pharmacological activity [ 11 , 12 , 13 ]. Experiments on germ-free (GF) animals showed that gut microbiota and its metabolites are implicated in the regulation of expression of a host’s hepatic cytochromes P450 (CYPs) [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of DSS-Induced Ulcerative Colitis and Butyrate on the Cytochrome P450 2A5: Contribution of the Microbiome

Satka

Frybortova

Zapletalová

et al. 2022

IJMS

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Several studies have indicated the beneficial anti-inflammatory effect of butyrate in inflammatory bowel disease (IBD) therapy implying attempts to increase butyrate production in the gut through orally administered dietary supplementation. Through the gut–liver axis, however, butyrate may reach directly the liver and influence the drug-metabolizing ability of hepatic enzymes, and, indirectly, also the outcome of applied pharmacotherapy. The focus of our study was on the liver microsomal cytochrome P450 (CYP) 2A5, which is a mouse orthologue of human CYP2A6 responsible for metabolism of metronidazole, an antibiotic used to treat IBD. Our findings revealed that specific pathogen-free (SPF) and germ-free (GF) mice with dextran sulfate sodium (DSS)-induced colitis varied markedly in enzyme activity of CYP2A and responded differently to butyrate pre-treatment. A significant decrease (to 50%) of the CYP2A activity was observed in SPF mice with colitis; however, an administration of butyrate prior to DSS reversed this inhibition effect. This phenomenon was not observed in GF mice. The results highlight an important role of gut microbiota in the regulation of CYP2A under inflammatory conditions. Due to the role of CYP2A in metronidazole metabolism, this phenomenon may have an impact on the IBD therapy. Butyrate administration, hence, brings promising therapeutic potential for improving symptoms of gut inflammation; however, possible interactions with drug metabolism need to be further studied.

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Gut microbiome affects the metabolism of metronidazole in mice through regulation of hepatic cytochromes P450 expression

Cited by 9 publications

References 36 publications

Exploration of Maternal and Fetal Toxicity Risks for Metronidazole-Related Teratogenicity and Hepatotoxicity through an Assessment in Albino Rats

Exploration of Maternal and Fetal Toxicity Risks for Metronidazole-Related Teratogenicity and Hepatotoxicity through an Assessment in Albino Rats

Butyrate Treatment of DSS-Induced Ulcerative Colitis Affects the Hepatic Drug Metabolism in Mice

Effect of DSS-Induced Ulcerative Colitis and Butyrate on the Cytochrome P450 2A5: Contribution of the Microbiome

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