Abstract
Triptolide (TP) is a major active component in Tripterygium root, but its therapeutic window was very narrow due to its severe multi-organ toxicity. In this work, the effect of TP combined with glycyrrhetic acid (GA) on mRNA expression and activity of four cytochrome P450 (CYP) enzymes in rat liver was studied after intragastric administration of TP (0.05, 0.3 and 0.6 mg x kg(-1) x day(-1)) and TP (0.6 mg x kg(-1) x day(-1)) combined with GA (30 mg x kg(-1) x day(-1)) for 7 consecutive days. Compared with the control, the high dose of TP significantly up-regulated the mRNA expression levels of CYP2E1, 1A2, 3A1 and 2C11, the co-administration of TP and GA further up-regulated the mRNA expression levels of CYP3A1, 2C11 and 2E1 as compared with the high dose of TP. Meanwhile, TP at high dose and combined with GA significantly increased CYP3A-associated testosterone 6beta-hydroxylation activity (2.2-fold and 4.1-fold, respectively) as compared with the control. Because TP is mainly metabolized by CYP3A2 in male rats, the present work indicated that TP-induced increase of CYP3A activity might be an important reason for the rapidly metabolic clearance of TP in rat liver, and GA can reduce the hepatotoxicity of TP by promoting its hepatic metabolic clearance. Furthermore, the results also suggest that the drug interactions might be occurred when TP and GA were co-administered with other CYP3A substrate drug.
MeSH terms
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Animals
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Aryl Hydrocarbon Hydroxylases / genetics
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Aryl Hydrocarbon Hydroxylases / metabolism
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Cytochrome P-450 CYP1A2 / genetics
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Cytochrome P-450 CYP1A2 / metabolism
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Cytochrome P-450 CYP2E1 / genetics
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Cytochrome P-450 CYP2E1 / metabolism
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Cytochrome P-450 CYP3A / genetics
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Cytochrome P-450 CYP3A / metabolism
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P-450 Enzyme System / metabolism*
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Cytochrome P450 Family 2
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Diterpenes / administration & dosage
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Diterpenes / isolation & purification
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Diterpenes / pharmacology*
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Dose-Response Relationship, Drug
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Drug Combinations
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Drug Interactions
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Enzyme Activation
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Epoxy Compounds / administration & dosage
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Epoxy Compounds / isolation & purification
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Epoxy Compounds / pharmacology
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Glycyrrhetinic Acid / isolation & purification
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Glycyrrhetinic Acid / pharmacology*
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Liver / enzymology*
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Male
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Phenanthrenes / administration & dosage
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Phenanthrenes / isolation & purification
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Phenanthrenes / pharmacology*
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Plant Roots / chemistry
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Plants, Medicinal / chemistry
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RNA, Messenger / metabolism
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Rats
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Rats, Wistar
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Steroid 16-alpha-Hydroxylase / genetics
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Steroid 16-alpha-Hydroxylase / metabolism
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Tripterygium / chemistry
Substances
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Diterpenes
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Drug Combinations
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Epoxy Compounds
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Phenanthrenes
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RNA, Messenger
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triptolide
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Cytochrome P-450 Enzyme System
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Cytochrome P-450 CYP2E1
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Aryl Hydrocarbon Hydroxylases
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CYP2C11 protein, rat
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Cyp3a23-3a1 protein, rat
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Cytochrome P-450 CYP1A2
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Cytochrome P-450 CYP3A
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Cytochrome P450 Family 2
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Steroid 16-alpha-Hydroxylase
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Glycyrrhetinic Acid