Species comparison in P450 induction: effects of dexamethasone, omeprazole, and rifampin on P450 isoforms 1A and 3A in primary cultured hepatocytes from man, Sprague-Dawley rat, minipig, and beagle dog.

Induction of P450 isoforms 1A (CYP1A) and 3A (CYP3A) by model inducers dexamethasone, omeprazole and rifampin was evaluated in primary cultured hepatocytes from man and laboratory animals. Inducer-specific species-differences were observed. Results with human hepatocytes from six human donors consistently show that both rifampin and dexamethasone were inducers of CYP3A activity (measured as testosterone 6beta-hydroxylase activity), with rifampin being more potent. Conversely, in rat hepatocytes, dexamethasone was a potent CYP3A inducer while rifampin was not an inducer. Rifampin but not dexamethasone induced CYP3A in minipig and beagle dog hepatocytes. Omeprazole was a potent inducer of CYP1A activity (measured as ethoxyresorufin-O-deethylase activity) in human, beagle dog and minipig hepatocytes, and not an inducer in rat hepatocytes. The species-differences observed suggest that human hepatocytes represent the most appropriate preclinical experimental system for the evaluation of P450 induction in human.

[1]  J. Gugenheim,et al.  Comparative effects of rifabutin and rifampicin on cytochromes P450 and UDP-glucuronosyl-transferases expression in fresh and cryopreserved human hepatocytes. , 1999, Chemico-biological interactions.

[2]  E. Roberts,et al.  Extended primary culture of human hepatocytes in a collagen gel sandwich system , 1997, In Vitro Cellular & Developmental Biology - Animal.

[3]  R. Remmel,et al.  Induction of the metabolism of midazolam by rifampin in cultured porcine hepatocytes: preliminary evidence for CYP3A isoforms in pigs. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[4]  A. Li,et al.  Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin. , 1997, Chemico-biological interactions.

[5]  B. Kennedy,et al.  Refinement of an in vitro cell model for cytochrome P450 induction. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[6]  A. Li,et al.  Optimization of cryopreservation procedures for rat and human hepatocytes. , 1989, Xenobiotica; the fate of foreign compounds in biological systems.

[7]  Y. Nishibe,et al.  Induction of cytochrome P450 3A (CYP 3A) by E 5110, a non-steroidal anti-inflammatory agent (NSAID), and typical CYP 3A inducers in primary cultures of dog hepatocytes. , 1995, Biological & pharmaceutical bulletin.

[8]  P. Maurel,et al.  Omeprazole is an aryl hydrocarbon-like inducer of human hepatic cytochrome P450. , 1990, Gastroenterology.

[9]  C. Friis,et al.  Pig hepatocytes as an in vitro model to study the regulation of human CYP3A4: prediction of drug-drug interactions with 17 alpha-ethynylestradiol. , 1997, Chemico-biological interactions.

[10]  P. Maurel,et al.  Cyclosporin A drug interactions. Screening for inducers and inhibitors of cytochrome P-450 (cyclosporin A oxidase) in primary cultures of human hepatocytes and in liver microsomes. , 1990, Drug metabolism and disposition: the biological fate of chemicals.

[11]  P. Beaune,et al.  Expression of cytochrome P-450 enzymes in cultured human hepatocytes. , 1990, European journal of biochemistry.

[12]  T. Harauchi,et al.  Effect of P-450 inducers on glutathione (GSH) depletion by bromobenzene in primary cultures of dog hepatocytes. , 1994, Biological & pharmaceutical bulletin.

[13]  G. Williams,et al.  Phenobarbital mechanistic data and risk assessment: enzyme induction, enhanced cell proliferation, and tumor promotion. , 1996, Pharmacology & therapeutics.

[14]  L. Benet,et al.  Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction , 1992, Clinical pharmacology and therapeutics.

[15]  L E Babiss,et al.  Transcriptional regulation of the albumin gene in cultured rat hepatocytes. Role of basement-membrane matrix. , 1990, Molecular biology & medicine.

[16]  Y. Berger,et al.  Expression and induction of CYP1A1/1A2, CYP2A6 and CYP3A4 in primary cultures of human hepatocytes: a 10-year follow-up , 2000, Xenobiotica; the fate of foreign compounds in biological systems.

[17]  D. Morris,et al.  Analysis of cytochrome P450 and phase II conjugating enzyme expression in adult male rat hepatocytes , 1999, In Vitro Cellular & Developmental Biology - Animal.

[18]  M. Strolin Benedetti,et al.  Induction and autoinduction properties of rifamycin derivatives: a review of animal and human studies. , 1994, Environmental health perspectives.

[19]  P. Seglen.  Hepatocyte suspensions and cultures as tools in experimental carcinogenesis. , 1979, Journal of toxicology and environmental health.

[20]  M. T. Donato,et al.  Effect of xenobiotics on monooxygenase activities in cultured human hepatocytes. , 1990, Biochemical pharmacology.