Induction of hepatic cytochrome P450 enzymes: methods, mechanisms, recommendations, and<b><i>in vitro–in vivo</i></b>correlations

Hewitt, Nicola J.; LeCluyse, Edward L.; Ferguson, Stephen S. G.

doi:10.1080/00498250701534893

Cited by 155 publications

(96 citation statements)

References 106 publications

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“…The results demonstrated that our hiHs not only expressed phase I and II enzymes, as well as phase III proteins, but also appeared to express a functional biotransforming system, shown by the cellular uptake, conjunction, and excretion of ICG. Moreover, some nuclear receptors, key mediators regulating drug-metabolizing enzymes and transporters [21], were also expressed by our hiHs. Importantly, metabolic function of our hiHs was enhanced by two common inducers; responding to compounds/inducers is characteristic of functioning hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Highly Efficient Differentiation of Functional Hepatocytes From Human Induced Pluripotent Stem Cells

Duan

Tschudy-Seney

et al. 2013

Stem Cells Translational Medicine

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Human induced pluripotent stem cells (hiPSCs) hold great potential for use in regenerative medicine, novel drug development, and disease progression/developmental studies. Here, we report highly efficient differentiation of hiPSCs toward a relatively homogeneous population of functional hepatocytes. hiPSC-derived hepatocytes (hiHs) not only showed a high expression of hepatocyte-specific proteins and liver-specific functions, but they also developed a functional biotransformation system including phase I and II metabolizing enzymes and phase III transporters. Nuclear receptors, which are critical for regulating the expression of metabolizing enzymes, were also expressed in hiHs. hiHs also responded to different compounds/inducers of cytochrome P450 as mature hepatocytes do. To follow up on this observation, we analyzed the drug metabolizing capacity of hiHs in real time using a novel ultraperformance liquid chromatography-tandem mass spectrometry. We found that, like freshly isolated primary human hepatocytes, the seven major metabolic pathways of the drug bufuralol were found in hiHs. In addition, transplanted hiHs engrafted, integrated, and proliferated in livers of an immune-deficient mouse model, and secreted human albumin, indicating that hiHs also function in vivo. In conclusion, we have generated a method for the efficient generation of hepatocytes from induced pluripotent stem cells in vitro and in vivo, and it appears that the cells function similarly to primary human hepatocytes, including developing a complete metabolic function. These results represent a significant step toward using patient/disease-specific hepatocytes for cell-based therapeutics as well as for pharmacology and toxicology studies. STEM CELLS TRANS- LATIONAL MEDICINE 2013;2:409 -419

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Section: Discussionmentioning

confidence: 99%

Highly Efficient Differentiation of Functional Hepatocytes From Human Induced Pluripotent Stem Cells

Duan

Tschudy-Seney

et al. 2013

Stem Cells Translational Medicine

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“…Extrapolation of findings related to the CYP3A subfamily from humans to animals is problematic. For example, CYP3A4 is highly inducible through PXR ligand binding (Hewitt et al 2007;Jones et al 2000) and only weakly induced through CAR in humans (Faucette et al 2006), in contrast with induction of CYP3A by both PXR and CAR in rodents (Graham and Lake 2008). Even within human populations, CYP3A4 inductive responses vary widely (Hewitt et al 2007;Wilkinson 1996).…”

Section: Hepatobiliary Biomarker Findings In Association With Prototymentioning

confidence: 99%

“…For example, CYP3A4 is highly inducible through PXR ligand binding (Hewitt et al 2007;Jones et al 2000) and only weakly induced through CAR in humans (Faucette et al 2006), in contrast with induction of CYP3A by both PXR and CAR in rodents (Graham and Lake 2008). Even within human populations, CYP3A4 inductive responses vary widely (Hewitt et al 2007;Wilkinson 1996). Beyond inter-individual differences in exposure to inducers, age, obesity, and even exercise level may affect CYP3A4 activity (Anderson 2008;Kotlyar and Carson 1999;Meijer et al 2001).…”

Section: Hepatobiliary Biomarker Findings In Association With Prototymentioning

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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“…However, significant speciesspecific differences in this response are common as are the pharmacologic/toxicologic consequences of the induction (Hewitt, Lecluyse, and Ferguson 2007). Common changes associated with hepatic enzyme induction include increased liver weight and hepatocellular hypertrophy, which are generally considered adaptive changes (Greaves 2007).…”

Section: Introductionmentioning

confidence: 99%

Effects of Lersivirine on Canine and Rodent Thyroid Function

et al. 2013

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Lersivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) being developed for the treatment of HIV-1 infection. Like other NNRTIs, lersivirine is a potent enzyme inducer in rodents capable of inducing a number of hepatic enzymes including those involved in its own metabolism. Preclinically lersivirine has been associated with hepatocellular hypertrophy and thyroid gland follicular cell hypertrophy in rats, mice, and dogs. In rodents, we show that development of thyroid hypertrophy is related to the classic mechanism, namely increased thyroxine (T4) clearance secondary to induction of uridine-diphosphoglucuronosyltransferase (UDPGT) in the liver and a resulting increase in thyroidstimulating hormone. Similarly, lersivirine-exposed dogs exhibit a significant increase in hepatic UDPGT enzyme activity along with increased T4 clearance although clear effects on serum thyroid hormone levels were less apparent. These effects on thyroid hormonal clearance in the dog suggest that thyroid gland hypertrophy in this species is due to the same mechanism shown to occur in rodents although, as expected, dogs better adapt to these effects and therefore maintain relatively normal thyroid hormonal balance. It is also notable that the minimal thyroid follicular hypertrophy that occurs in dogs does not progress as is seen in rodents. As is the case with rodents, these adaptive changes in the dog are not considered indicative of a human health risk.

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Induction of hepatic cytochrome P450 enzymes: methods, mechanisms, recommendations, andin vitro–in vivocorrelations

Cited by 155 publications

References 106 publications

Highly Efficient Differentiation of Functional Hepatocytes From Human Induced Pluripotent Stem Cells

Highly Efficient Differentiation of Functional Hepatocytes From Human Induced Pluripotent Stem Cells

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

Effects of Lersivirine on Canine and Rodent Thyroid Function

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