Transcriptional profiling of genes induced in the livers of patients treated with carbamazepine.
BACKGROUND
The antiepileptic drug carbamazepine (CBZ) is a potent inducer of human drug metabolism, resulting in serious interactions with many commonly prescribed drugs. The molecular mechanisms underlying this response are not well understood, however, and the spectrum of CBZ-inducible genes in human liver has not been thoroughly investigated.


METHODS
The availability of liver ribonucleic acid from 2 epileptic patients treated with CBZ and from 7 control subjects enabled us to study the global induction response of drug-metabolizing enzymes, drug transporters, and nuclear receptors in vivo.


RESULTS
Using expression profiling, we identified 64 significantly up-regulated transcripts but only 1 significantly down-regulated transcript (SLC22A5). We confirmed the induction of several genes that previously have been shown to be inducible by drugs in vitro, including multiple cytochrome P450 (CYP) genes in the CYP1A, CYP2A, CYP2B, CYP2C, and CYP3A subfamilies, as well as glutathione S-transferase A1, uridine diphosphate-glucuronosyltransferase 1As, the drug transporter ABCC2, and the nuclear receptors CAR (constitutive androstane receptor) and PXR (pregnane X receptor). Moreover, we identified a number of additional genes not previously known to be induced by CBZ, including CYP39A1, sulfotransferase 1A1, glutathione S-transferase Z1, and the drug transporters SLCO1A2, ABCG2, and ABCB7, as well as the glucocorticoid and aldosterone receptors. In transactivation studies in CV-1 cells, we demonstrated that both CBZ and its major metabolite, CBZ-10,11-epoxide, activate the nuclear receptor PXR in a concentration-dependent fashion and at therapeutic concentrations with 50% inhibitory concentration values of approximately 50 micromol/L.


CONCLUSIONS
CBZ is a potent inducer of a broad spectrum of drug-metabolizing enzymes and drug transporters in the human liver, and these effects are mediated at least in part by activation of PXR.
Oscarson
Mikael
M
Division of Pharmacology/Neurobiology, Biozentrum, University of Basel, Basel, Switzerland.
Zanger
Ulrich M
UM
Rifki
Oktay F
OF
Klein
Kathrin
K
Eichelbaum
Michel
M
Meyer
Urs A
UA
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D002220:Carbamazepine / Q000494:pharmacology* / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D050216:Metabolic Detoxication, Phase I / Q000235:genetics; D050217:Metabolic Detoxication, Phase II / Q000235:genetics; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics
C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; D000927:Anticonvulsants; D000089762:Multidrug Resistance-Associated Protein 2; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D002220:Carbamazepine; D003577:Cytochrome P-450 Enzyme System