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

doi:10.1016/S0169-409X(96)00417-6

Advanced Drug Delivery Reviews

Volume 22, Issues 1–2, 15 November 1996, Pages 105-132

https://doi.org/10.1016/S0169-409X(96)00417-6 Get rights and content

Abstract

Among the numerous enzyme systems involved in the metabolism of xenobiotics, cytochromes P450 (CYP) from families CYP1, 2 and 3 play a prominent role. These cytochromes are monoxygenases mainly expressed in the liver. They are able to oxidize an apparently unlimited number of compounds and, on some occasions, generate cytotoxic or genotoxic metabolites responsible for various pathologies including hepatitis and chemical carcinogenesis. The expression and function of these cytochromes might be affected by a number of factors including, physiological (hormones, growth factors, cytokines, etc.), pathological (infections, inflammation, hepatectomy, etc.), genetic (polymorphism of expression or function) and environmental (drugs, diet compounds, pollutants) factors. These various properties account for the wide interindividual variability exhibited by the human populations in response to drugs and environmental pollutants in terms of metabolism and toxicity. From the analysis of a number of clinical reports focusing on adverse drug effects and from the above considerations, it appears that answering the following questions is absolutely required before a new drug is administered to man with maximum safety: (1) What is the metabolic pathway of the drug and what are the main metabolites? (2) Which enzyme system is involved in the metabolism of the drug? (3) Is the drug an inducer or inhibitor of drug metabolizing enzymes? (4) What are the possible drug interactions? (5) Can the drug be activated to cytotoxic or genotoxic metabolites? In this chapter, I shall describe the various human hepatocyte culture systems used in this and other laboratories, and show how the use of these cultures, in combination with the other in vitro systems including human liver microsomes, may help to answer the above questions concerning several drugs including: diazepam, ketotifen, zolpidem, omeprazole, lansoprazole, cyclosporin A, clometacin and cyproterone acetate. Emphasis will be placed on the comparison between the results obtained in vitro and the situation in man in vivo, as well as on the prediction, confirmation and/or a posteriori explanation of clinical observations.

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

Abstract

Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

Trends Pharmacol. Sci.

J. Biol. Chem.

Arch. Biochem. Biophys.

Alcohol

Biochem. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

Arch. Biochem. Biophys.

Arch. Biochem. Biophys.

Gastroenterology

Biochem. Pharmacol.

Gastroenterology

Exp. Cell Res.

Life Sci.

Biochem. Pharmacol.

Biochem. Pharmacol.

The molecular biology of cytochrome P450s

Pharmacol. Rev.

The P450 superfamily: Update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature

DNA Cell Biol.

Cytochrome P450: progress and predictions

Faseb J.

Genotype or phenotype: the definition of a pharmacogenetic polymorphism

Pharmacogenetics

A form of cytochrome P450 in man, orthologous to form d in the rat, catalyses the O-deethylation of phenacetin and is inducible by cigarette smoking

Br. J. Clin. Pharmacol.

Characterization of roles of human cytochrome P-450 enzymes in carcinogen metabolism

Asia Pac. J. Pharmacol.

Human CYP1A1 gene: cosegregation of the enzyme inducibility phenotype and an RFLP

Am. J. Hum. Genet.

Genetic linkage of lung cancer-associated MspI polymorphisms with amino acid replacement in the heme binding region of the human cytochrome P450IA1 gene

J. Biochem.

Identification of the human liver cytochrome P450 responsible for coumarin 7-hydroxylase activity

Biochem. J.

Isolation and characterization of a cytochrome P450 of the IIA subfamily from human liver microsomes

Eur. J. Biochem.

Characterization of cytochrome P-450 2B6 in human liver microsomes

Drug Metab. Dispos.

Purification of two cytochrome P450 isozymes related to CYP2A and CYP3A gene families from monkey (baboon, Papio papio) liver microsomes. Cross reactivity with human forms

Eur. J. Biochem.

Enhanced activation of cyclophosphamide and ifosphamide in primary cultures of human hepatocytes treated with inducers of CYP2B, CYP2C and CYP3A

Characterization of cDNAs, mRNA, and proteins related to human liver microsomal cytochrome P450 (S)-mephenytoin 4′-hydroxylase

Biochemistry

Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions

Chem. Res. Toxicol.

Evidence that CYP2C19 is the major (S)-mephenytoin 4′-hydroxylase in humans

Biochemistry

Biochemistry and molecular biology of the human CYP2C subfamily

Pharmacogenetics

The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene and a pseudogene

Am. J. Hum. Genet.

Characterization of the common genetic defect in humans deficient in debrisoquine metabolism

Nature

Genetic polymorphism of cytochrome P450 CYP2D6 in Zimbabwean population

Pharmacogenetics

Debrisoquine/sparteine hydroxylation genotype and phenotype: analysis of common mutations and alleles of CYP2D6 in a European population

DNA Cell Biol.

Oxidative and reductive metabolism by cytochrome P450 2E1

Faseb J.

Modulation of cytochrome P450 isozymes in human liver by ethanol and drug intake

Eur. J. Clin. Invest.

The CYP3A family

Cytochrome P450 isoenzymes, epoxide hydrolase and glutathione transferases in rat and human hepatic and extrahepatic tissues

J. Pharmacol. Exp. Ther.

The increase in urinary excretion of 6β-hydroxycortisol as a marker of human hepatic cytochrome P450 IIIA induction

Br. J. Clin. Pharmacol.

Cyclosporin A drug interactions. Screening for inducers and inhibitors of cytochrome P450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes

Drug Metab. Dispos.

Oxidative metabolism of lansoprazole by human liver cytochromes P450

Mol. Pharmacol.

Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver

Pharmacogenetics

Studies on the expression and metabolic capability of human liver cytochrome P450IIIA5 (HLp3)

Mol. Pharmacol.

Molecular cloning and sequence analysis of cDNA containing the entire coding region for human fetal liver cytochrome P450

J. Biochem. (Tokyo)