Abstract
Hepatic CYP1A especially CYP1A2 plays an important role in the reduction of aristolochic acid I (AAI) nephrotoxicity. In this study, we investigated the effects of tanshinone I, a strong inducer of Cyp1a, on the nephrotoxicity induced by AAI. Histopathology and blood biochemistry assays showed that tanshinone I could reduce AAI-induced acute kidney injury. Pharmacokinetics analysis revealed that tanshinone I markedly decreased AUC of AAI in plasma and the content of AAI in both liver and kidney, indicating the enhancement of AAI metabolism. Real-time PCR and Western blot analysis confirmed that tanshinone I effectively increased the mRNA and protein levels of hepatic CYP1A1 and CYP1A2 in vivo. Luciferase assay showed that tanshinone I strongly increased the transcriptional activity of CYP1A1 and CYP1A2 in the similar extent. In summary, our data suggested that tanshinone I facilitated the metabolism of AAI and prevented AAI-induced kidney injury by induction of hepatic CYP1A 1/2 in vivo.
Keywords:
Aristolochic acid; CYP1A; Kidney injury; Tanshinone I.
Copyright © 2013 Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Abietanes / pharmacokinetics
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Abietanes / pharmacology*
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Animals
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Antineoplastic Agents, Phytogenic / pharmacokinetics
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Antineoplastic Agents, Phytogenic / pharmacology*
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Area Under Curve
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Aristolochic Acids / antagonists & inhibitors*
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Aristolochic Acids / pharmacokinetics
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Aristolochic Acids / toxicity*
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Blood Chemical Analysis
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Blotting, Western
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Carcinogens / antagonists & inhibitors*
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Carcinogens / pharmacokinetics
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Carcinogens / toxicity*
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Chromatography, High Pressure Liquid
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Cytochrome P-450 CYP1A1 / biosynthesis*
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Cytochrome P-450 CYP1A1 / metabolism
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Cytochrome P-450 CYP1A2 / biosynthesis*
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Cytochrome P-450 CYP1A2 / metabolism
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Enzyme Induction / drug effects
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Kidney / chemistry
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Kidney / metabolism
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Kidney / pathology
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Kidney Diseases / chemically induced*
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Kidney Diseases / enzymology*
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Kidney Diseases / pathology
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Liver / chemistry
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Liver / metabolism
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Luciferases / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Plasmids / genetics
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RNA / biosynthesis
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RNA / isolation & purification
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Real-Time Polymerase Chain Reaction
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Spectrophotometry, Ultraviolet
Substances
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Abietanes
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Antineoplastic Agents, Phytogenic
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Aristolochic Acids
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Carcinogens
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tanshinone
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RNA
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aristolochic acid I
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Luciferases
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Cytochrome P-450 CYP1A1
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Cytochrome P-450 CYP1A2