Induction of CYP3A4 and MDR1 gene expression by baicalin, baicalein, chlorogenic  acid, and ginsenoside Rf through constitutive androstane receptor- and pregnane X  receptor-mediated pathways.
The herbal products baicalin, baicalein, chlorogenic acid, and ginsenoside Rf have multiple pharmacological effects and are extensively used in alternative and/or complementary therapies. The present study investigated whether baicalin, baicalein, chlorogenic acid, and ginsenoside Rf induced the expression of the cytochrome P450 3A4 (CYP3A4) and multi-drug resistance 1 (MDR1) genes through the pregnane X receptor and constitutive androstane receptor pathways. Real time PCR, western blotting, and a luminescent assay were used to assess the induction of gene expression and activity of CYP3A4 and MDR1 by the test compounds. The interactions of baicalein/chlorogenic acid/ginsenoside Rf with constitutive androstane receptor and pregnane X receptor were evaluated using luciferase reporter and gel shift assays. Baicalein induced the expression of CYP3A4 and MDR1 mRNA by activating pregnane X receptor and constitutive androstane receptor. Chlorogenic acid and ginsenoside Rf showed a relatively weak effect on CYP3A4 promoter activation only in HepG2 cells cotransfected with constitutive androstane receptor and demonstrated no effects on MDR1 via either the constitutive androstane receptor or pregnane X receptor pathway. Baicalin had no effect on either CYP3A4 or MDR1 gene expression. In conclusion, baicalein has the potential to up-regulate CYP3A4 and MDR1 through the direct activation of the constitutive androstane receptor and pregnane X receptor pathways. Chlorogenic acid and ginsenoside Rf only induced constitutive androstane receptor-mediated CYP3A4 expression.
Li
Yue
Y
Department of New Drug Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, and Institute of Infectious Diseases, Beijing Ditan Hospital, No. 1, Xian Nong Tan Street, Beijing 100050, China. liyued104@126.com
Wang
Qi
Q
Yao
Xiaomin
X
Li
Yan
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002726:Chlorogenic Acid / Q000494:pharmacology; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D044950:Flavanones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D036145:Ginsenosides / Q000494:pharmacology; D006801:Humans; D010936:Plant Extracts / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D047488:Retinoid X Receptors / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000090702:Constitutive Androstane Receptor; D044950:Flavanones; D005419:Flavonoids; D036145:Ginsenosides; D010936:Plant Extracts; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; D002726:Chlorogenic Acid; C038044:baicalin; C006680:baicalein; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C055328:ginsenoside Rf