Cytochrome P450 3A expression and function in liver and intestinal mucosa from dexamethasone‐treated sheep

Maté, María Laura; Lifschitz, Adrián Luis; Sallovitz, Juan Manuel; Ballent, Mariana; Muscher, A. S.; Wilkens, Mirja R.; Schröder, Bernd; Lanusse, Carlos; Virkel, G.

doi:10.1111/j.1365-2885.2011.01334.x

Cited by 9 publications

(7 citation statements)

References 42 publications

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“…To fully evaluate and understand the possible clinical impact of these findings, the interaction of butyrate and certain drugs such as erythromycin was studied. Due to its exclusive hepatic metabolism, erythromycin is among the preferred substrates for testing the metabolic activity of the CYP3A subfamily in food‐producing species (Maté et al ., ). Erythromycin alone caused an increased expression of both CYP2H1 and CYP3A37 genes, while CYP1A was not affected in vitro .…”

Section: Discussionmentioning

confidence: 97%

Effects of dietary sodium butyrate on hepatic biotransformation and pharmacokinetics of erythromycin in chickens

Csikó

Nagy

Mátis

et al. 2014

Vet Pharm & Therapeutics

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Butyrate, a commonly applied feed additive in poultry nutrition, can modify the expression of certain genes, including those encoding cytochrome P450 (CYP) enzymes. In comparative in vitro and in vivo experiments, the effect of butyrate on hepatic CYP genes was examined in primary cultures of chicken hepatocytes and in liver samples of chickens collected from animals that had been given butyrate as a feed additive. Moreover, the effect of butyrate on the biotransformation of erythromycin, a marker substance for the activity of enzymes of the CYP3A family, was investigated in vitro and in vivo. Butyrate increased the expression of the avian-specific CYP2H1 both in vitro and in vivo. In contrast, the avian CYP3A37 expression was decreased in hepatocytes following butyrate exposure, but not in the in vivo model. CYP1A was suppressed by butyrate in the in vitro experiments, and overexpressed in vivo in butyrate-fed animals. The concomitant incubation of hepatocytes with butyrate and erythromycin led to an increased CYP2H1 expression and a less pronounced inhibition of CYP3A37. In in vivo pharmacokinetic experiments, butyrate-fed animals given a single i.m. injection of erythromycin, a slower absorption phase (longer T(half-abs) and delayed T(max)) but a rapid elimination phase of this marker substrate was observed. Although these measurable differences were detected in the pharmacokinetics of erythromycin, it is unlikely that a concomitant application of sodium butyrate with erythromycin or other CYP substrates will cause clinically significant feed-drug interaction in chickens.

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Section: Discussionmentioning

confidence: 97%

Effects of dietary sodium butyrate on hepatic biotransformation and pharmacokinetics of erythromycin in chickens

Csikó

Nagy

Mátis

et al. 2014

Vet Pharm & Therapeutics

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“…However, the hepatic CYP‐dependent S‐oxidation of MNP was higher (around 3.7‐fold) in sheep compared to cattle (see Table ). A survey of the available bibliography showed that hepatic CYP contents are between 0.64–0.91 nmol per mg of microsomal protein in sheep (Calléja et al ., ; Maté et al ., ) and 0.65–0.81 nmol/mg in cattle (Nebbia et al ., ; Giantin et al ., ). Based on these reported CYP contents in both species, it might be possible to estimate the CYP‐dependent S‐oxidation of MNP as turnover number (nmol/min·nmol of CYP).…”

Section: Discussionmentioning

confidence: 99%

Hepatic biotransformation pathways and ruminal metabolic stability of the novel anthelmintic monepantel in sheep and cattle

Ballent

Virkel

Maté

et al. 2016

Vet Pharm & Therapeutics

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Monepantel (MNP) is a new amino-acetonitrile derivative anthelmintic drug used for the treatment of gastrointestinal (GI) nematodes in sheep. The present work investigated the main enzymatic pathways involved in the hepatic biotransformation of MNP in sheep and cattle. The metabolic stability in ruminal fluid of both the parent drug and its main metabolite (monepantel sulphone, MNPSO2 ) was characterized as well. Additionally, the relative distribution of both anthelmintic molecules between the fluid and particulate phases of the ruminal content was studied. Liver microsomal fractions from six (6) rams and five (5) steers were incubated with a 40 μm of MNP. Heat pretreatment (50 °C for 2 min) of liver microsomes was performed for inactivation of the flavin-monooxygenase (FMO) system. Additionally, MNP was incubated in the presence of 4, 40, and 80 μm of methimazole (MTZ), a FMO inhibitor, or equimolar concentrations of piperonyl butoxide (PBx), a well-known general cytochrome P450 (CYP) inhibitor. In both ruminant species, MNPSO2 was the main metabolite detected after MNP incubation with liver microsomes. The conversion rate of MNP into MNPSO2 was fivefold higher (P < 0.05) in sheep (0.15 ± 0.08 nmol/min·mg) compared to cattle. In sheep, the relative involvement of both FMO and CYP systems (FMO/CYP) was 36/64. Virtually, only the CYP system appeared to be involved in the production of MNPSO2 in cattle liver. Methimazole significantly reduced (41 to 79%) the rate of MNPSO2 production in sheep liver microsomes whereas it did not inhibit MNP oxidation in cattle liver microsomes. On the other hand, PBx inhibited the production of MNPSO2 in liver microsomes of both sheep (58 to 98%, in a dose-dependent manner) and cattle (almost 100%, independently of the PBx concentration added). The incubation of MNP and MNPSO2 with ruminal contents of both species showed a high chemical stability without evident metabolism and/or degradation as well as an extensive degree of adsorption (83% to 90%) to the solid phase of the ruminal content. Overall, these results are a further contribution to the understanding of the metabolic fate of this anthelmintic drug in ruminants.

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“…Dexamethasone is considered an inducer of CYP3A4[ 34 ]. In sheep small intestine, dexamethasone caused a significant enhancement of CYP3A apoprotein level in the duodenal mucosa[ 35 ]. Thus, we suggest that dexamethasone played an important role in the excellent CYP450 expression in the serum-free medium.…”

Section: Discussionmentioning

confidence: 99%

Novel sericin-based hepatocyte serum-free medium and sericin’s effect on hepatocyte transcriptome

Huang¹,

Peng²,

Li³

et al. 2018

WJG

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AIMTo develop a novel hepatocyte serum-free medium based on sericin, and to explore the effect of sericin on the hepatocyte transcriptome.METHODSA controlled trial comparing novel serum-free medium and other media: C3A cells were cultured in our novel serum-free medium, HepatoZYME, complete medium (DMEM/F12 with 100 mL/L FBS), and DMEM/F12, and then cell attachment, proliferation, and function as well as the biocompatibility of the media were assessed. A comparative study of serum-free media with or without 2 mg/mL sericin: the effect of sericin on C3A growth was assessed by cell viability and proliferation, the effect of sericin on C3A cell cycle distribution was determined by flow cytometry, and the effect of sericin on the C3A transcriptome was assessed by gene-chip array and RT-qPCR.RESULTSMore C3A cells attached to the plate containing our serum-free medium than to those containing HepatoZYME and DMEM/F12 at 24 h post-seeding. Both the viability and proliferation rate of C3A cells in sericin-based serum-free medium were superior to those of cells in HepatoZYME and DMEM/F12 (P < 0.001). The content of albumin and urea in our serum-free medium was significantly higher than that in HepatoZYME and DMEM/F12 throughout the whole culture period (P < 0.001) and was similar to that in complete medium at day 3, 4, and 5. In part 2, cell viability and proliferation were greater in the presence of 2 mg/mL sericin (P < 0.001), as was the proportion of cells in S phase (16.21% ± 0.98% vs 12.61% ± 0.90%, P < 0.01). Gene-chip array analysis indicated that the expression of CCR6, EGFR, and FOS were up-regulated by 2 mg/mL sericin, and RT-qPCR revealed that the expression of CCR6, EGFR, FOS, AKT1, JNK1, NFkB1, MMP-9, MEK2, ERK1/2 and MYC was up-regulated by 2 mg/mL sericin (P < 0.05).CONCLUSIONWe developed a novel hepatocyte serum-free medium. Sericin probably enhances cell attachment through the CCR6-Akt-JNK-NF-κB pathway and promotes cell proliferation through CCR6-mediated activation of the ERK1/2-MAPK pathway.

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Cytochrome P450 3A expression and function in liver and intestinal mucosa from dexamethasone‐treated sheep

Cited by 9 publications

References 42 publications

Effects of dietary sodium butyrate on hepatic biotransformation and pharmacokinetics of erythromycin in chickens

Effects of dietary sodium butyrate on hepatic biotransformation and pharmacokinetics of erythromycin in chickens

Hepatic biotransformation pathways and ruminal metabolic stability of the novel anthelmintic monepantel in sheep and cattle

Novel sericin-based hepatocyte serum-free medium and sericin’s effect on hepatocyte transcriptome

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