Comparison of Inducibility of Sulfotransferase and UDP-Glucuronosyltransferase mRNAs by Prototypical Microsomal Enzyme Inducers in Primary Cultures of Human and Cynomolgus Monkey Hepatocytes

Nishimura, Masuhiro; Koeda, Akiko; Shimizu, Takefumi; Nakayama, Mitsuo; Satoh, Tetsuo; Narimatsu, Shizuo; Naito, Shinsaku

doi:10.2133/dmpk.23.45

Cited by 19 publications

(22 citation statements)

References 23 publications

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“…It has been reported that PB is an inducer of GSTA1/2 (Morel et al, 1993) and that OME and RIF are inducers of UGT1A1 (Nishimura et al, 2008). Note that the -fold inductions of these two genes with the three inducers were much lower than those observed with P450s, ranging mostly between 1.5-and 5-fold, with the exception of UGT1A1 induction by PB and OME that reached 7 to 10-fold (Table 1).…”

Section: Discussionmentioning

confidence: 72%

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Stable Expression, Activity, and Inducibility of Cytochromes P450 in Differentiated HepaRG Cells

Anthérieu

Chesné²,

Li³

et al. 2009

Drug Metab Dispos

234

143

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ABSTRACT:HepaRG cells possess the unique property to differentiate in vitro and to express various functions of mature hepatocytes, including the major cytochromes P450 (P450s). In the present study, we carefully analyzed mRNA expression and activity of the major P450s and their responsiveness to three prototypical inducers, phenobarbital, rifampicin, and omeprazole, in differentiated HepaRG cell cultures over a 4-week period after low and high seeding. Only minor differences were observed in P450 activities when measured by two cocktails of probe substrates, probably related to the choice and/or concentration of substrates. Similar results were obtained from the two cell seeding conditions. Expression and activities of several P450s were dimethyl sulfoxidedependent. However, basal P450 expression and activities as well as their responsiveness to the prototypical inducers were well maintained over the 4-week period, and a good correlation was observed between transcript levels and corresponding activities. Thus, CYP1A2, CYP2B6, and CYP3A4 were found to accurately respond to their respective prototypical inducers, i.e., omeprazole, phenobarbital, and rifampicin. Likewise, basal expression of several phase II enzymes, transporters, and nuclear receptors, and response to inducers were also well preserved. More genes were found to be induced in HepaRG cells than in primary human hepatocytes, and no marked variation was noticed between the different passages. Taken together, these data support the conclusion that HepaRG cells represent a promising surrogate to primary human hepatocytes for xenobiotic metabolism and toxicity studies.

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Section: Discussionmentioning

confidence: 72%

“…However only limited studies still exist on the regulation of UGTs in human hepatocytes (Soars et al, 2004;Nishimura et al, 2008). We show that in addition to the major P450s, several phase II enzymes and transporters were modulated by PB, RIF, and/or OME.…”

Section: Discussionmentioning

confidence: 82%

Stable Expression, Activity, and Inducibility of Cytochromes P450 in Differentiated HepaRG Cells

Anthérieu

Chesné²,

Li³

et al. 2009

Drug Metab Dispos

234

143

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“…Animal models are variable in their relevance for study of these reproductive effects (Taubøll et al 2008). Rationale for the use of nonhuman primates, specifically cynomolgus monkeys, as models for the effects of DME induction on steroid reproductive hormone phase II metabolism has been presented (Barbier and Bélanger 2003;Nishimura et al 2008). 822 ENNULAT ET AL.…”

Section: Endogenous Reproductive Hormone Effects Associated With Protmentioning

confidence: 99%

Effects of Hepatic Drug-metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man

et al. 2010

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Hepatic drug-metabolizing enzyme (DME) induction is an adaptive response associated with changes in preclinical species; this response can include increases in liver weight, hepatocellular hyperplasia and hypertrophy, and upregulated tissue expression of DMEs. Effects of DME induction on clinical pathology markers of hepatobiliary injury and function in animals as well as humans are not well established. This component of a multipart review of the comparative pathology of xenobiotically mediated induction of hepatic metabolizing enzymes reviews pertinent data from retrospective and prospective preclinical and clinical studies. Particular attention is given to studies with confirmation of DME induction and concurrent evaluation of liver and/or serum hepatobiliary marker enzyme activities and histopathology. These results collectively indicate that in the rat, when histologic findings are limited to hepatocellular hypertrophy, DME induction is not expected to be associated with consistent or substantive changes in serum or plasma activity of hepatobiliary marker enzymes such as alanine aminotransferase, alkaline phosphatase, and gamma glutamyltransferase. In the dog and the monkey, published studies also do not demonstrate a consistent relationship across DME-inducing agents and changes in these clinical pathology parameters. However, increased liver alkaline phosphatase or gamma glutamyltransferase activity in dogs treated with phenobarbital or corticosteroids suggests that direct or indirect induction of select hepatobiliary injury markers can occur both in the absence of liver injury and independently of induction of DME activity. Although correlations between tissue and serum levels of these hepatobiliary markers are limited and inconsistent, increases in serum/plasma activities that are substantial or involve changes in other markers generally reflect hepatobiliary insult rather than DME induction. Extrahepatic effects, including disruption of the hypothalamic-pituitary-thyroid axis, can also occur as a direct outcome of hepatic DME induction in humans and animals. Importantly, hepatic DME induction and associated changes in preclinical species are not necessarily predictive of the occurrence, magnitude, or enzyme induction profile in humans.

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“…Isolation of Cynomolgus Monkey Hepatocytes Perfusion of the cynomolgus monkey liver was performed according to the Seglen method 13) with some modifications. 14,15) The hepatocytes obtained were stored in liquid nitrogen until use.…”

Section: Comparison Of Inducibility Of Multidrug Resistance (Mdr)1 Mmentioning

confidence: 99%

“…14,15) Human cell suspensions with viability rates of 90 to 94 as assessed by trypan blue dye exclusion and cynomolgus monkey cell suspensions with viability rates of 80 to 92 as assessed by the same method were used for the experiments. The hepatocytes were used for experiments at 48 h after inoculation.…”

Section: Monolayer Culture Of Human and Cynomolgus Monkey Hepatocytesmentioning

confidence: 99%

Comparison of Inducibility of Multidrug Resistance (MDR)1, Multidrug Resistance-Associated Protein (MRP)1, and MRP2 mRNAs by Prototypical Microsomal Enzyme Inducers in Primary Cultures of Human and Cynomolgus Monkey Hepatocytes

Nishimura

Koeda²,

Morikawa³

et al. 2008

Biological & Pharmaceutical Bulletin

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Multidrug resistance 1 (MDR1, p-glycoprotein (P-gp), ABCB1) was the first human ATP binding cassette (ABC) transporter whose cDNA was cloned and characterized based on its ability to confer a multidrug-resistance phenotype to cancer cells. 1) Multidrug resistance-associated protein 1 (MRP1, ABCC1) and multidrug resistance-associated protein 2 (MRP2, ABCC2) have been identified as multidrug-resistance genes and demonstrated to transport glutathione conjugates of many toxic compounds.2,3) The tissue localization of MDR1 includes the choroid plexus (so-called bloodbrain barrier), adrenal gland, kidney, intestine, and liver; that of MRP1 is ubiquitous (but low in the liver); and that of MRP2 includes the kidney, intestine, and liver. [2][3][4] . Several in vivo studies have demonstrated that the expression of ABC transporters such as MDR1, MRP1, and MRP2 is up-or down-regulated by chemical compounds and nutrients in the rat 5,6) and mouse 7,8) liver. Several in vitro studies using human hepatocytes have demonstrated that the expression of ABC transporters such as MDR1 is up-regulated by microsomal enzyme inducers such as rifampicin (Rif) and dexamethasone (Dex).9,10) Furthermore, we have previously described a method for evaluating the mRNA induction of transporters following exposure to microsomal enzyme inducers and candidate drugs in primary cultures of human and rat hepatocytes.11,12) However, few studies have investigated the evaluation of MDR1, MRP1, and MRP2 mRNA expression in cynomolgus monkeys following exposure to drugs, although cynomolgus monkeys have commonly been employed in studies of drug metabolism and toxicity. Furthermore, evaluation employing cynomolgus monkeys as well as evaluation employing rats has been performed in numerous preclinical studies. In order to ensure that the results of preclinical studies involving evaluation by in vitro methods using primary cultures of hepatocytes are applicable to clinical studies, it is important to evaluate the information obtained by the primary culture of both human and cynomolgus monkey hepatocytes. The present study was therefore conducted to compare the inducibility of MDR1, MRP1, and MRP2 mRNAs following exposure to the prototypical microsomal enzyme inducers Rif, Dex, and omeprazole (Ome) in primary cultures of cryopreserved hepatocytes obtained from humans and cynomolgus monkeys. Research and Development Center, Otsuka Pharmaceutical Factory, Inc.; Japan: b Ina Research Inc.; Nishiminowa, Ina, Japan: c Ichikawa General Hospital; Ichikawa, Japan: and d Laboratory of Health Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University; Tsushima-naka, Okayama 700-8530, Japan. Received June 23, 2008; accepted September 8, 2008; published online September 8, 2008 This study investigated the changes in the mRNA levels of the ATP binding cassette (ABC) transporters multidrug resistance 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and multidrug resistance-associated protein 2 (MRP2) following ex...

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Comparison of Inducibility of Sulfotransferase and UDP-Glucuronosyltransferase mRNAs by Prototypical Microsomal Enzyme Inducers in Primary Cultures of Human and Cynomolgus Monkey Hepatocytes

Cited by 19 publications

References 23 publications

Stable Expression, Activity, and Inducibility of Cytochromes P450 in Differentiated HepaRG Cells

Stable Expression, Activity, and Inducibility of Cytochromes P450 in Differentiated HepaRG Cells

Effects of Hepatic Drug-metabolizing Enzyme Induction on Clinical Pathology Parameters in Animals and Man

Comparison of Inducibility of Multidrug Resistance (MDR)1, Multidrug Resistance-Associated Protein (MRP)1, and MRP2 mRNAs by Prototypical Microsomal Enzyme Inducers in Primary Cultures of Human and Cynomolgus Monkey Hepatocytes

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