Induction of drug metabolism: Species differences and toxicological relevance

doi:10.1016/j.tox.2008.09.002

Toxicology

Volume 254, Issue 3, 30 December 2008, Pages 184-191

https://doi.org/10.1016/j.tox.2008.09.002 Get rights and content

Abstract

A large number of drugs and other chemicals have been shown to induce hepatic microsomal cytochrome P450 (CYP) forms in experimental animals and humans. Most CYP forms are induced by receptor-mediated mechanisms leading to an increase in gene transcription. Important nuclear receptors involved in the induction of CYP1A, CYP2B, CYP3A and CYP4A subfamily forms comprise, respectively, the aryl hydrocarbon receptor, the constitutive androstane receptor, the pregnane X receptor and the peroxisome proliferator-activated receptor alpha. Hepatic CYP form induction can be assessed by in vivo, ex vivo and in vitro methods. Significant species differences can exist in the enzyme induction response to a given chemical and also in the toxicological consequences of induction. Hepatic CYP form induction in humans may lead to clinically important drug–drug interactions. In rodents hepatic CYP form induction can be associated with the formation of tumours by non-genotoxic modes of action in the liver, thyroid and other tissues.

Introduction

Enzyme induction is a process in which a chemical (e.g. a drug) induces (i.e. initiates or enhances) the expression of an enzyme. Mammalian cytochrome P450 (CYP) forms have a major role in the oxidative metabolism of drugs, other xenobiotics and certain endogenous compounds (Ioannides, 2008, Parkinson, 2001). CYP-dependent enzyme activities can be either induced or inhibited by a variety of chemicals including some therapeutic agents (Dickins, 2004, Lin, 2006, Pelkonen et al., 1998).

The concept of induction of hepatic drug and xenobiotic metabolising enzymes has been known for many years. Early examples of known inducers include phenobarbitone (phenobarbital) and other drugs, pesticides and polycyclic aromatic hydrocarbons (Conney, 1967, Parke, 1968). It is now well established that hepatic xenobiotic metabolising enzymes in both experimental animals and humans can be induced by a wide range of therapeutic agents, pesticides, food additives, industrial chemicals, natural products and environmental pollutants (Conney, 1986, Okey, 1990, Pelkonen et al., 1998). Moreover, hepatic xenobiotic metabolising enzymes can also be stimulated by cigarette smoking, alcohol intake and by dietary factors including consumption of a high protein/low carbohydrate diet, barbecued meat, cruciferous vegetables and herbal preparations such as St. John’s Wort (Hewitt et al., 2007a, Parkinson, 2001, Pelkonen et al., 1998, Verhoeven et al., 1997).

This review will consider hepatic CYP forms, mechanisms of induction of CYP forms, methods to assess CYP form induction and species differences in response. The consequences of CYP form induction with respect to drug–drug interactions in humans and liver and thyroid tumour formation in experimental animals will be described.

Section snippets

Hepatic CYP forms

Mammalian hepatic CYP forms are found in the mitochondria (involved in steroid hormone biosynthesis and vitamin D metabolism) and in the endoplasmic reticulum (Parkinson, 2001). Hepatic CYP forms involved in the metabolism of therapeutic agents and other chemicals are primarily localised in the endoplasmic reticulum and following homogenisation of the liver and differential centrifugation of the liver whole homogenate, are recovered in the microsomal fraction. In human liver microsomal CYP

Mechanisms of induction of hepatic CYP forms

Most CYP forms are induced by receptor-mediated mechanisms leading to an increase in gene transcription (Dickins, 2004, Lin, 2006, Ma, 2008). Important nuclear receptors involved in the induction of CYP1A, CYP2B, CYP3A and CYP4A subfamily forms comprise, respectively, the aryl hydrocarbon receptor (AhR), the constitutive androstane receptor (CAR), the pregnane X receptor (PXR) and the peroxisome proliferator-activated receptor alpha (PPARα). The AhR is a member of the Per-Arnt Sim (PAS) family

Methods to assess induction of hepatic CYP forms

As described in Section 5, species differences can exist between the effects of CYP form inducers in rodents and humans. Hence, while a rodent CYP form inducer may also have the potential to induce CYP forms in human liver this will need to be confirmed by studies with human systems. Should a compound be a potent inducer of hepatic CYP2B or CYP4A forms in rodents, this may result in tumour formation in bioassay studies (see Section 7).

Hepatic CYP induction in experimental animals can be

Species differences in hepatic CYP form induction

Although the induction of hepatic CYP forms observed in rodent safety evaluation studies may indicate a potential for induction of CYP forms in human liver, significant species differences in the induction of hepatic CYP forms have been reported (Dickins, 2004, Hewitt et al., 2007a, Hewitt et al., 2007b, Lin, 2006). Moreover, the transcription factors described above are known to be the molecular basis of such species differences. For example, the observed species differences between both CAR

Clinical consequences of hepatic CYP form induction

Therapeutic agents which produce hepatic CYP induction may stimulate their own metabolism by autoinduction. For compounds active in their parent form induction may increase elimination and hence reduce the desired pharmacological effect, whereas for prodrugs enhanced formation of the active metabolite(s) may result in an increased pharmacological effect.

An important consequence of drug–drug interactions is where one drug produces induction which results in the enhanced metabolism of a

Formation of tumours in rodents by CYP form inducers

The induction of hepatic microsomal CYP forms in rodents (i.e. rats and mice) by non-genotoxic NCEs can be associated in chronic studies with the formation of tumours in the liver and other tissues. For example, CYP2B inducers can produce liver and thyroid tumours and CYP4A inducers liver, pancreas and testis tumours (Holsapple et al., 2006, Klaunig et al., 2003, Meek et al., 2003). Hepatic CYP form induction in rodent liver should thus be considered part of a pleiotropic response to the

Conflict of interest

There are no competing interests.

Acknowledgements

This paper is dedicated to the memory of Professor Gordon G. Gibson, who was a valued colleague of both authors and who died shortly after the British Toxicology Society (BTS) meeting at which this paper was presented. Gordon Gibson will be remembered for his eminent work on the application of molecular biology techniques to the study of the metabolism and toxicity of xenobiotics. Along with Professor Peter Goldfarb he set up the first molecular toxicology group in the UK at the University of

References (90)

P. Bentley et al.
Hepatic peroxisome proliferation in rodents and its significance for humans
Food Chem. Toxicol.
(1993)
A.I. Choudhury et al.
Molecular analysis of peroxisome proliferation in the hamster
Toxicol. Appl. Pharmacol.
(2004)
A.H. Conney
Induction of microsomal cytochrome P-450 enzymes: the first Bernard B Brodie Lecture at Pennsylvania State University
Life Sci.
(1986)
J. Doull et al.
A cancer risk assessment of di(2-ethylhexyl)phthalate: application of the new U.S. EPA Risk assessment Guidelines
Regul. Toxiocol. Pharmacol.
(1999)
F.J. Gonzalez et al.
PPARα: mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators
Toxicology
(2008)
P. Grasso et al.
Evidence for and possible mechanisms of non-genotoxic carcinogenesis in rodent liver
Mutat. Res.
(1991)
S.C. Hasmall et al.
The perturbation of apoptosis and mitosis by drugs and xenobiotics
Pharmacol. Ther.
(1999)
N.J. Hewitt et al.
Induction of drug metabolizing enzymes: a survey of in vitro methodologies and interpretations used in the pharmaceutical industry—do they comply with FDA recommendations?
Chem. -Biol. Interact.
(2007)
M. Katoh et al.
Chimeric mice with humanized liver
Toxicology
(2008)
B.G. Lake et al.
Comparative studies on nafenopin-induced hepatic peroxisome proliferation in the rat, Syrian hamster, guinea pig and marmoset
Toxicol. Appl. Pharmacol.
(1989)

B.G. Lake et al.

Species differences in hepatic peroxisome proliferation, cell replication and transforming growth factor β1 gene expression in the rat, Syrian hamster and guinea pig

Mutat. Res.

(2000)

E.L. LeCluyse

Human hepatocyte culture systems for the in vitro evaluation of cytochrome P450 expression and regulation

Eur. J. Pharm. Sci.

(2001)

P. Maurel

The use of adult human hepatocytes in primary culture and other in vitro systems to investigate drug metabolism in man

Adv. Drug Del. Rev.

(1996)

J.T. Moore et al.

Functional and structural comparison of PXR and CAR

Biochim. Biophys. Acta

(2003)

L.B. Moore et al.

Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands

J. Biol. Chem.

(2000)

A.B. Okey

Enzyme induction in the cytochrome P-450 system

Pharmacol. Ther.

(1990)

A. Parkinson et al.

The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes

Toxicol. Appl. Pharmacol.

(2004)

V.O. Pustylnyak et al.

Comparative study of CYP2B induction in the liver of rats and mice by different compounds

Life Sci.

(2007)

L. Richert et al.

Effects of clofibric acid on mRNA expression profiles in primary cultures of rat, mouse and human hepatocytes

Toxicol. Appl. Pharmacol.

(2003)

D.-Y. Ryu et al.

Regulation of hepatic CYP1A isozymes by piperonyl butoxide and acenaphthylene in the mouse

Chem. -Biol. Interact.

(1997)

D.T.H. Verhoeven et al.

A review of mechanisms underlying anticarcinogenicity by brassica vegetables

Chem. -Biol. Interact.

(1997)

J. Whysner et al.

Phenobarbital mechanistic data and risk assessment: enzyme induction, enhanced cell proliferation, and tumor promotion

Pharmacol. Ther.

(1996)

L. Xu et al.

2,3,7,8,Tetrachlorodibenzo-p-dioxin induction of cytochrome P4501A in cultured rat and human hepatocytes

Chem. Biol. Interact.

(2000)

T.K. Baker et al.

Modulation of gap junctional intercellular communication in rodent, monkey and human hepatocyte by nongenotoxic compounds

Prog. Clin. Biol. Res.

(1995)

A.R. Boobis et al.

IPCS framework for analyzing the relevance of a cancer mode of action for humans

Crit. Rev. Toxicol.

(2006)

C.C. Capen

Toxic responses of the endocrine system

C. Cheung et al.

Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor-α

Cancer Res.

(2004)

A.H. Conney

Pharmacological implications of microsomal enzyme induction

Pharmacol. Rev.

(1967)

S. Coecke et al.

The use of long-term hepatocyte cultures for detecting induction of drug metabolising enzymes: the current status. ECVAM Hepatocytes and Metabolically Competent Systems Task Force Report 1

ATLA

(1999)

S.M. Cohen et al.

Evaluating the human relevance of chemically induced animal tumors

Toxicol. Sci.

(2004)

S.M. Cohen et al.

The human relevance of information on carcinogenic modes of action: overview

Crit. Rev. Toxicol.

(2003)

P.G. Curran et al.

The effect of hepatic enzyme-inducing drugs on thyroid hormones and the thyroid gland

Endocr. Rev.

(1991)

M. Degawa et al.

Species differences among experimental rodents in induction of P450IA family enzymes by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Jpn. J. Cancer Res.

(1992)

M. Dickins

Induction of cytochromes P450

Curr. Top. Med. Chem.

(2004)

B.A. Diwan et al.

Enhancement of thyroid and hepatocarcinogenesis by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene in rats at doses that cause maximal induction of CYP2B

Carcinogenesis

(1996)

R.J. Edwards et al.

Induction of cytochrome P450 enzymes in cultured precision-cut human liver slices

Drug Metab. Dispos.

(2003)

W. El-Sankary et al.

Use of a reporter gene assay to predict and rank the potency and efficacy of CYP3A4 inducers

Drug Metab. Dispos.

(2001)

S. Gerbal-Chaloin et al.

Induction of CYP2C genes in human hepatocytes in primary culture

Drug Metab. Dispos.

(2001)

G.G. Gibson et al.

Cytochrome P-450 induced by clofibrate. Purification and properties of a hepatic cytochrome P-450 relatively specific for the 12- and 11-hydroxylation of dodecanoic acid (lauric acid)

Biochem. J.

(1982)

R.A. Graham et al.

Cloning, tissue expression, and regulation of Beagle dog CYP4A genes

Toxicol. Sci.

(2006)

T. Hays et al.

Role of peroxisome proliferator-activated receptor-α (PPARα) in bezafibrate-induced hepatocarcinogenesis and cholestasis

Carcinogenesis

(2005)

N.J. Hewitt et al.

Induction of hepatic cytochrome P450 enzymes: methods, mechanisms, recommendations, and in vitro–in vivo correlations

Xenobiotica

(2007)

N.J. Hewitt et al.

Primary hepatocytes: current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies

Drug Metab. Rev.

(2007)

R.N. Hill et al.

Risk assessment of thyroid follicular cell tumors

Environ. Health Perspect.

(1998)

M.P. Holsapple et al.

Mode of action in relevance of rodent liver tumors to human cancer risk

Toxicol. Sci.

(2006)

Cited by (119)

Comparative analysis of YAP/TEAD inhibitors in 2D and 3D cultures of primary human hepatocytes reveals a novel non-canonical mechanism of CYP induction
2023, Biochemical Pharmacology
Induction of cytochrome P450 (CYP) genes constitutes an important cause of drug–drug interactions and preclinical evaluation of induction liability is mandatory for novel drug candidates. YAP/TEAD signaling has emerged as an attractive target for various oncological indications and multiple chemically distinct YAP/TEAD inhibitors are rapidly progressing towards clinical stages. Here, we tested the liability for CYP induction of a diverse set of YAP/TEAD inhibitors with different modes of action and TEAD isoform selectivity profiles in monolayers and 3D spheroids of primary human hepatocytes (PHH). We found that YAP/TEAD inhibition resulted in broad induction of CYPs in 2D monolayers, whereas, if at all, only marginal induction was seen in spheroid culture. Comprehensive RNA-Seq indicated that YAP/TEAD signaling was increased in 2D culture compared to spheroids, which was paralleled by elevated activities of the interacting transcription factors LXR and ESRRA, likely at least in part due to altered mechanosensing. Inhibition of this YAP/TEAD hyperactivation resulted in an overall reduction of hepatocyte dedifferentiation marked by increased hepatic functionality, including CYPs. These results thus demonstrate that the observed induction is due to on-target effects of the compounds rather than direct activation of xenobiotic sensing nuclear receptors. Combined, the presented data link hepatocyte dedifferentiation to YAP/TEAD dysregulation, reveal a novel non-canonical pathway of CYP induction and highlight the advantage of organotypic 3D cultures to predict clinically relevant pharmacokinetic properties, particularly for atypical induction mechanisms.
Metabolism-mediated drug–drug interactions – Study design, data analysis, and implications for in vitro evaluations
2022, Medicine in Drug Discovery
Therapeutics undergo metabolism as a major biotransformation pathway for their bioactivation or clearance from the body, which is a well-known factor for affecting drug pharmacokinetics, safety and efficacy. Drug metabolism primarily occurs in the liver and intestine, where expressing a wide variety of drug metabolizing enzymes, which are generally divided into Phase I enzymes like cytochrome P450s (CYP450s) and Phase II enzymes as UDP glucuronosyltransferases (UGTs). The chemical structures of therapeutic molecules are modified, which are called metabolites, as outcome of oxidation or conjugation by metabolism or biotransformation. Therefore, metabolism-mediated drug–drug interactions (MMDDI) may have more potential clinical significance than transporter-mediated drug–drug interactions (TMDDI), because both parent molecules and metabolites may contribute to the drug–drug interaction which may make the clinical significance more complicated. This article reviewed the challenges of MMDDI during therapeutic innovations, and industry solutions for supporting IND/NDA submissions according to the related guidances by the regulatory agencies as NMPA, FDA, PMDA and EMA.
Quantitative protein profiling of phenobarbital-induced drug metabolizing enzymes in rat liver by liquid chromatography mass spectrometry using formalin-fixed paraffin-embedded samples
2021, Journal of Pharmacological and Toxicological Methods
Citation Excerpt :
Phenobarbital induces phase I DMEs by activating nuclear receptors, constitutive androstane receptor (CAR), and pregnancy X receptor (PXR). While there is cross-talk between nuclear receptor functions, Cyp2b and Cyp3a forms are known to be induced by CAR and PXR, respectively (Graham & Lake, 2008). The present protein expression data also indicated prominent induction of Cyp2b2 and Cyp3a1.
Administration of a compound can induce drug-metabolizing enzymes (DMEs) in the liver. DME induction can affect various parameters in toxicology studies. Therefore, evaluation of DME induction is important for interpreting test compound-induced biological responses. Several methods such as measurement of hepatic microsomal DME activity using substrates, electron microscopy, or immunohistochemistry have been used; however, these methods are limited in throughput and specificity or are not quantitative. Liquid chromatography mass spectrometry (LC/MS)-based protein analysis can detect and quantify multiple proteins simultaneously per assay. Studies have shown that formalin-fixed paraffin-embedded (FFPE) samples, which are routinely collected in toxicology studies, can be used for LC/MS-based protein analysis. To validate the utility of LC/MS using FFPE samples for quantitative evaluation of DME induction, we treated rats with a DME inducer, phenobarbital, and compared the protein expression levels of 13 phase-I and 11 phase-II DMEs between FFPE and fresh frozen hepatic samples using LC/MS. A good correlation between data from FFPE and frozen samples was obtained after analysis. In FFPE and frozen samples, the expression of 6 phase-I and 8 phase-II DMEs showed a similar significant increase and a prominent rise in Cyp2b2 and Cyp3a1 levels. In addition, LC/MS data were consistent with the measurement of microsomal DME activities. These results suggest that LC/MS-based protein expression analysis using FFPE samples is as effective as that using frozen samples for detecting DME induction.
Pesticide mixture effects on liver protein abundance in HepaRG cells
2021, Toxicology
Toxicological effects of chemicals are mostly tested individually. However, consumers encounter exposure to complex mixtures, for example multiple pesticide residues, by consuming food such as crops, fruits or vegetables. Currently, more than 450 active substances are approved in the European Union, and there is little data on effects after combined exposure to several pesticides. Toxicological animal studies would increase enormously, if pesticide combinations had to be analyzed in vivo. Therefore, in vitro methods addressing this issue are needed. We have developed 32 immunoaffinity-based mass spectrometry assays to investigate the impact of hepatotoxic active substances on liver proteins in human HepaRG cells. Five compounds were selected based on their (dis)similar capability to modulate protein levels, and on their combined use in commercially available formulations. Four binary mixtures were prepared from these five substances and tested in different concentrations over three time points. We applied a novel statistical method to describe deviations from additivity and to detect antagonistic and synergistic effects. The results regarding the abundance of hepatotoxicity-related proteins showed additive behavior for 1323 out of 1427 endpoints tested, while 104 combinatorial effects deviating from additivity, such as antagonism or synergism were observed.
Commiphora myrrha (Nees) Engl. resin extracts induce phase-I cytochrome P450 2C8, 2C9, 2C19, and 3A4 isoenzyme expressions in human hepatocellular carcinoma (HepG2) cells
2021, Saudi Pharmaceutical Journal
Commiphora myrrha (Nees) Engl. (C. myrrha) resin is the most Middle Eastern herbal medicine used against numerous diseases. After being decocted or macerated, this resin is widely consumed among Saudi Arabian patients who are already under prescribed medication. Despite its popularity, no studies have been reported on potential modulation effects of these resin extracts on drug metabolism. Therefore, we studied C. myrrha resin extracts on the expression of cytochrome P450 (CYP) drug-metabolizing isoenzyme in human hepatocellular carcinoma cell line HepG2. The C. myrrha extracts were prepared by sonication and boiling, resembling the most popular traditional preparations of maceration and decoction, respectively. Both boiled and sonicated aqueous extracts were fingerprinted using high-performance liquid chromatography equipped with ultra-violet detector (HPLC-UVD). The viability of HepG2 cells treated with these aqueous extracts was determined using CellTiter-Glo® assay in order to select the efficient and non-toxic resin extract concentrations for phase-I metabolic CYP isoenzyme expression analysis. The isoenzyme gene and protein expression levels of CYP 2C8, 2C9, 2C19, and 3A4 were assessed using reverse transcription-quantitative polymerase chain reaction and Western blot technologies. The HPLC-UVD fingerprinting revealed different chromatograms for C. myrrha boiled and sonicated aqueous extracts. Both aqueous extracts were toxic to HepG2 cells when tested at concentrations exceeding 150 µg/ml of the dry crude extract. The CYP 2C8, 2C9, and 2C19 mRNA expression levels increased up to 4.0-fold in HepG2 cells treated with either boiled or sonicated C. myrrha aqueous extracts tested between 1 and 30 µg/ml, as compared with the untreated cells. However, CYP3A4 mRNA expression level exceeded the 2.0-fold cutoff when the cells were exposed to 30 µg/ml of C. myrrha extracts. The up-regulation of CYP mRNA expression levels induced by both boiled and sonicated C. myrrha aqueous extracts was confirmed at the CYP protein expression levels. In conclusion, both sonicated and boiled C. myrrha aqueous extracts modulate CYP 2C8, 2C9, 2C19, and 3A4 gene expression at clinically-relevant concentrations regardless of preparation methods. Further in vitro and in vivo experiments are required for CYP isoenzyme activity assessment and the establishment of herb-drug interaction profile for these traditional medicinal resin extracts.
Generation of uniform liver spheroids from human pluripotent stem cells for imaging-based drug toxicity analysis
2021, Biomaterials
Recent advances in pluripotent stem cell technology provide an alternative source of human hepatocytes to overcome the limitations of current toxicity tests. However, this approach requires optimization and standardization before it can be used as a fast and reliable toxicity screening system. Here, we designed and tested microwell culture platforms with various diameters. We found that large quantities of uniformly-sized hepatocyte-like cell (HLC) spheroids (3D-uniHLC-Ss) could be efficiently and reproducibly generated in a short period time from a small number of differentiating human pluripotent stem cells (hPSCs). The hPSC-3D-uniHLC-Ss that were produced in 500-μm diameter microwells consistently exhibited high expressions of hepatic marker genes and had no significant signs of cell death. Importantly, a hepatic master gene hepatocyte nuclear factor 4α (HNF4α) was maintained at high levels, and the epithelial-mesenchymal transition was significantly attenuated in hPSC-3D-uniHLC-Ss. Additionally, when compared with 3D-HLC-Ss that were produced in other 3D platforms, hPSC-3D-uniHLC-Ss showed significantly higher hepatic gene expressions and drug-metabolizing activity of the enzyme, CYP3A4. Imaging-based drug toxicity studies demonstrated that hPSC-3D-uniHLC-Ss exhibited enhanced sensitivity to various hepatotoxicants, compared to HLCs, which were differentiated under 2D conditions. Precise prediction of drug-induced hepatotoxicity is a crucial step in the early phases of drug discovery. Thus, the hPSC-3D-uniHLC-Ss produced using our microwell platform could be used as an imaging-based toxicity screening system to predict drug hepatotoxicity.

View all citing articles on Scopus

View full text

ReviewInduction of drug metabolism: Species differences and toxicological relevance

Abstract

Introduction

Section snippets

Hepatic CYP forms

Mechanisms of induction of hepatic CYP forms

Methods to assess induction of hepatic CYP forms

Species differences in hepatic CYP form induction

Clinical consequences of hepatic CYP form induction

Formation of tumours in rodents by CYP form inducers

Conflict of interest

Acknowledgements

Food Chem. Toxicol.

Toxicol. Appl. Pharmacol.

Life Sci.

Regul. Toxiocol. Pharmacol.

Toxicology

Mutat. Res.

Pharmacol. Ther.

Chem. -Biol. Interact.

Toxicology

Toxicol. Appl. Pharmacol.

Mutat. Res.

Eur. J. Pharm. Sci.

Adv. Drug Del. Rev.

Biochim. Biophys. Acta

J. Biol. Chem.

Pharmacol. Ther.

Toxicol. Appl. Pharmacol.

Life Sci.

Toxicol. Appl. Pharmacol.

Chem. -Biol. Interact.

Chem. -Biol. Interact.

Pharmacol. Ther.

Chem. Biol. Interact.

Modulation of gap junctional intercellular communication in rodent, monkey and human hepatocyte by nongenotoxic compounds

Prog. Clin. Biol. Res.

IPCS framework for analyzing the relevance of a cancer mode of action for humans

Crit. Rev. Toxicol.

Toxic responses of the endocrine system

Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor-α

Cancer Res.

Pharmacological implications of microsomal enzyme induction

Pharmacol. Rev.

The use of long-term hepatocyte cultures for detecting induction of drug metabolising enzymes: the current status. ECVAM Hepatocytes and Metabolically Competent Systems Task Force Report 1

ATLA

Evaluating the human relevance of chemically induced animal tumors

Toxicol. Sci.

The human relevance of information on carcinogenic modes of action: overview

Crit. Rev. Toxicol.

The effect of hepatic enzyme-inducing drugs on thyroid hormones and the thyroid gland

Endocr. Rev.

Species differences among experimental rodents in induction of P450IA family enzymes by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Jpn. J. Cancer Res.

Induction of cytochromes P450

Curr. Top. Med. Chem.

Enhancement of thyroid and hepatocarcinogenesis by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene in rats at doses that cause maximal induction of CYP2B

Carcinogenesis

Induction of cytochrome P450 enzymes in cultured precision-cut human liver slices

Drug Metab. Dispos.

Use of a reporter gene assay to predict and rank the potency and efficacy of CYP3A4 inducers

Drug Metab. Dispos.

Induction of CYP2C genes in human hepatocytes in primary culture

Drug Metab. Dispos.

Cytochrome P-450 induced by clofibrate. Purification and properties of a hepatic cytochrome P-450 relatively specific for the 12- and 11-hydroxylation of dodecanoic acid (lauric acid)

Biochem. J.

Cloning, tissue expression, and regulation of Beagle dog CYP4A genes

Toxicol. Sci.

Role of peroxisome proliferator-activated receptor-α (PPARα) in bezafibrate-induced hepatocarcinogenesis and cholestasis

Carcinogenesis

Induction of hepatic cytochrome P450 enzymes: methods, mechanisms, recommendations, and in vitro–in vivo correlations

Xenobiotica

Primary hepatocytes: current understanding of the regulation of metabolic enzymes and transporter proteins, and pharmaceutical practice for the use of hepatocytes in metabolism, enzyme induction, transporter, clearance, and hepatotoxicity studies

Drug Metab. Rev.

Risk assessment of thyroid follicular cell tumors

Environ. Health Perspect.

Mode of action in relevance of rodent liver tumors to human cancer risk

Toxicol. Sci.

Review
Induction of drug metabolism: Species differences and toxicological relevance