Studies of xenobiotic biotransformation by in vitro techniques are destined to play an increasingly important role in assessing the safety and efficacy of drugs and other new chemical entities. The first part of this article summarizes some of the in vitro techniques that have been developed to evaluate xenobiotics as inducers of liver microsomal cytochrome P450. The second part provides an overview of reaction phenotyping, an in vitro technology for determining which human P450 enzyme or enzymes are involved in the biotransformation of xenobiotics.
Demoz A., Vaagenes H., Aarsaether N., Hvattum E., Skorve J., Gottlicher M., Lillehaug JR, Gibson GG, Gustafsson J-A., Hood S., and Berge RK (1994). Coordinate induction of hepatic fatty Acyl-CoA oxidase and P4504A1 in rat after activation of the peroxisome proliferator-activated receptor (PPAR) by sulphur-substituted fatty acid analogues. Xenobiotica24: 943-956.
2.
Diaz D., Fabre I., Daujat M., Saint Aubert B., Bories P., Michel H., and Maurel P. (1990). Omeprazole is an aryl hydrocarbon-like inducer of human hepatic cytochrome P450. Gastroenterology99: 737-747.
3.
Gandolfi AJ, Wijeweera J., and Brendel K. (1996). Use of precision-cut liver slices as an in vitro tool for evaluating liver function. Toxicol. Pathol. 24: 58-61.
4.
Gonzalez FJ (1989). The molecular biology of cytochrome P450s. Pharmacol. Rev. 40: 243-288.
5.
Grasso P., Sharratt M., and Cohen AJ (1991). Role of persistent, non-genotoxic tissue damage in rodent cancer and relevance to humans. Annu. Rev. Pharmacol. Toxicol. 31: 253-287.
6.
Grossman SJ, Herold EG, Drey JM, Alberts DW, Umbenhauer DR, Patrick DH, Nicoll-Griffith D., Chauret N., and Yergey JA (1993). CYP1A1 specificity of verlukast epoxidation in mice, rats, rhesus monkeys and humans. Drug Met. Dispos. 21: 1029-1036.
7.
Guengerich FP (1994). Catalytic selectivity of human cytochrome P450 enzymes: Relevance to drug metabolism and toxicity . Toxicol. Lett. 70: 133-138.
8.
Halpert JR, Guengerich FP, Bend JR, and Correia MA (1994). Contemporary issues in toxicology: Selective inhibitors of cytochromes P450. Toxicol. Appl. Pharmacol. 125: 163-175.
9.
Houston JB (1994). Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem. Pharmacol. 47: 1469-1479.
10.
Kato R. and Yamazoe Y. (1994). The importance of substrate concentration in determining cytochromes P450 therapeutically relevant in vivo. Pharmacogenetics4: 359-362.
11.
Kivsito KT, Neuvonen PJ, and Klotz U. (1994). Inhibition of terfenadine metabolism: Pharmacokinetic and pharmacodynamic consequences. Clin. Pharmacokin. 27: 1-5.
12.
Koop DR and Tierney DJ (1990). Multiple mechanisms in the regulation of ethanol-inducible cytochrome P450IIE1. BioEssays12: 429-435.
13.
LeCluyse EL , Audus KL, and Hochman JH (1994). Formation of extensive canalicular networks by rat hepatocytes cultured in collagenase-sandwich configuration . Am. J. Physiol. 266(Cell Physiol. 35): C1764-C1774.
14.
Liang Q., He J-S. and Fulco A. (1995). The role of Barbie box sequences as cis-acting elements involved in the barbiturate-mediated induction of cytochromes P450 BM-1 and P450 BM-3 in bacillus megaterium. J. Biol. Chem. 270: 4438-4450.
15.
Meyer UA (1994). The molecular basis of genetic polymorphisms of drug metabolism. J. Pharm. Pharmacol. 46 (suppl. 1): 409-415.
16.
Muerhoff AS , Griffin KJ, and Johnson EF (1992). The peroxisome proliferator-activated receptor mediates the induction of CYP4A6, a cytochrome P450 fatty acid ω-hydroxylase, by clofibric acid. J. Biol. Chem. 267: 19051-19053.
17.
Nebert D. (1994). Drug-metabolizing enzymes in ligand-modulated transcription. Biochem. Pharmacol. 47: 25-37.
18.
Nelson DR, Kamataki T., Waxman DJ, Guengerich FP, Estabrook RW, Feyerseisen R., Gonzalez FJ, Coon MJ, Gunsalus IC, Gotoh O., Okuda K., and Nebert DW (1993). The P450 superfamily: Update on new sequences, gene mapping, accession numbers, early trivial names, and nomenclature. DNA Cell Biol. 12: 1-51.
19.
Nguyen T., Rushmore TH, and Pickett CB (1994). Transcriptional regulation of a rat liver glutathione S-transferase ya subunit gene. J. Biol. Chem. 269: 13656-13663.
20.
Okey AB (1990). Enzyme induction in the cytochrome P450 system . Pharmacol. Ther. 45: 241-298.
21.
Parkinson A. and Hurwitz A. (1991). Omeprazole and the induction of human cytochrome P450: A response to concerns about potential adverse effects . Gastroenterology100: 1157-1164.
22.
Peck CC, Temple R., and Collins JM (1993). Understanding consequences of concurrent therapies . J. Am. Med. Assoc. 269: 1550-1552.
23.
Pichard L., Fabre I., Fabre G., Domergue J., Saint-Aubert B., Mourad G., and Maurel P. (1990). 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. 18: 595-606.
24.
Porter TD and Coon MJ (1991). Multiplicity of isoforms, substrates, and catalytic and regulatory mechanisms. J. Biol. Chem. 266: 13469-13472.
25.
Quattrochi LC and Tukey RH (1993). Nuclear uptake of the Ah (dioxin) receptor in response to omeprazole: Transcriptional activation of the human CYPIAl gene. Mol. Pharmacol. 43: 504-508.
26.
Ryan DE and Levin W. (1990). Purification and characterization of hepatic microsomal cytochrome P450. Pharmacol. Ther. 45: 153-239.
27.
Shimada T., Yamazaki H., Mimura M., Inui Y., and Guengerich FP (1994). Interindividual variations in human liver cytochrome P450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: Studies with liver microsomes of 30 Japanese and 30 Caucasians. J. Pharmacol. Exp. Ther. 270: 414-423.
28.
Sidhu JS, Farin FM, and Omiecinski CJ (1993). Influence of extracellular matrix overlay on phenobarbital mediated induction of CYP2B1, 2B2, and 3A1 gene in primary adult rat hepatocyte culture. Arch. Biochem. Biophys. 30: 103-113.
29.
Sonderfan AJ , Arlotto MP, Dutton DR, McMillen SK, and Parkinson A. (1987). Regulation of testosterone hydroxylation by rat liver microsomal cytochrome P450. Arch. Biochem. Biophys. 255: 27-41.
30.
Sundseth SS and Waxman DJ (1991). Sex-dependent expression and clofibrate inducibility of cytochrome P450 4A fatty acid w-hydroxylases . J. Biol. Chem. 267: 3915-3921.
31.
Thomas P., Reidy J., Reik L., Ryan D., Koop D., and Levin W. (1984). Use of monoclonal and polyclonal antibody probes against rat hepatic cytochromes P450c and P450d to detect immunochemically related isozymes in liver microsomes from different species. Arch. Biochem. Biophys. 235: 239-253.
32.
Tucker GT (1994). Clinical implications of genetic polymorphism in drug metabolism. J. Pharm. Pharmacol. 46(suppl.1): 417-424.
33.
Waxman DJ, Pampori NA, Ram PA, Agrawal AK, and Shapiro BH (1991). Interpulse interval in circulating growth hormone patterns regulates sexually dimorphic expression of hepatic cytochrome P450 . Biochemistry88: 6868-6872.
Wrighton SA and Stevens JC (1992). The human hepatic cytochromes P450 involved in drug metabolism. Crit. Rev. Toxicol. 22: 1-21.
36.
Wrighton SA, Vandenbranden M., Stevens JC, Shipley LA, Ring, BJ, Rettie AE, and Cashman JR (1993). In vitro methods for assessing human hepatic drug metabolism: Their use in drug development. Drug Metab. Rev . 25: 453-484.
37.
Zand R.Sidney. N., Slattery J.Thummel K.Kalhorn T.Adams S., and Wright J. (1993) Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans. Clin. Pharmacol. Ther. 54: 142-149.