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Vol. 61, Issue 1, 1-6, January 2002
Pharmacogenetics Section, Laboratory of Reproductive and
Developmental Toxicology (A.U., Y.Y., T.S., M.N.) and National
Institute of Environmental Health Sciences (NIEHS) Microarray Center
(H.K.H., C.A.A.); Laboratory of Molecular Carcinogenesis, NIEHS,
National Institutes of Health, Research Triangle Park, North Carolina;
and Tularik, South San Francisco, California (H.K.W.,
J.M.L.)
Phenobarbital (PB) induces various gene encoding
drug/steroid-metabolizing enzymes such as cytochromes P450 (P450s)
and transferases. Although the nuclear orphan constitutive
active receptor (CAR) has been identified as a key transcription factor
that regulates the induction of CYP2B, the full scope of CAR-regulated
genes still remains a major question. To this end, reverse
transcriptase-polymerase chain reaction and cDNA microarray
techniques were employed to examine gene expression in wild-type and
CAR-null mice. The results show that a total of 138 genes were detected
to be either induced or repressed in response to PB treatment, of which
about half were under CAR regulation. Including CYP2B10, CYP3A11,
and NADPH-CYP reductase, CAR regulated a group of the PB-induced
drug/steroid-metabolizing enzymes. Enzymes such as amino
levulinate synthase 1 and squalene epoxidase displayed CAR-independent
induction by PB. Cyp4a10 and Cyp4a14
represented the group of genes induced by PB only in CAR-null mice,
indicating that CAR may be a transcription blocker that prevents these
genes from being induced by PB. Additionally, the group of genes
encoding enzymes and proteins involved in basic biological processes
such as energy metabolism underwent the CAR-dependent repression by PB.
Thus, CAR seems to have diverse roles, both as a positive and negative
regulator, in the regulation of hepatic genes in response to PB beyond
drug/steroid metabolism.
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