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Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
Effect of troglitazone on CYP1A1 induction.
Hyung Gyun Kim1, Eun Hee Han, Hye Gwang Jeong
1BK21 Project Team, Department of Pharmacy, College of Pharmacy, Research Center for Proteineous Materials, Chosun University, 375 Seosuk-dong, Gwangju 501-759, South Korea.
Toxicology
|March 1, 2008
Summary
Troglitazone boosts CYP1A1 gene expression and enzyme activity by activating peroxisome proliferator-activated receptor-gamma (PPAR-gamma). This mechanism, involving a specific DNA response element, may contribute to carcinogenesis.
Area of Science:
- Pharmacology
- Molecular Biology
- Toxicology
Background:
- Peroxisome proliferators are known to increase CYP1A1 activity, but the underlying mechanisms are not fully understood.
- CYP1A1 plays a crucial role in metabolizing xenobiotics and procarcinogens.
Purpose of the Study:
- To investigate the effect of troglitazone, a PPAR-gamma agonist, on CYP1A1 gene expression and activity.
- To elucidate the molecular mechanisms by which troglitazone influences CYP1A1.
Main Methods:
- Dose-response studies of troglitazone on CYP1A1 mRNA and EROD activity.
- PPAR antagonist (GW9662) treatment to assess PPAR-gamma involvement.
- Luciferase reporter assays and deletion mutagenesis of the CYP1A1 promoter.
- Electrophoretic mobility shift assays (EMSA) to study PPAR-gamma binding to PPRE.
Main Results:
- Troglitazone significantly increased CYP1A1 mRNA levels and EROD activity in a dose-dependent manner.
- The troglitazone-induced EROD activity was attenuated by a PPAR antagonist.
- A functional PPRE in the CYP1A1 promoter was identified, mediating troglitazone's inductive effect.
- Troglitazone activated PPAR-gamma, enabling specific binding to the CYP1A1 PPRE, and increased BaP-DNA adduct formation.
Conclusions:
- Troglitazone induces CYP1A1 enzyme activity and gene expression via PPAR-gamma activation.
- The identified PPRE in the CYP1A1 promoter is critical for this induction.
- Troglitazone-mediated CYP1A1 induction may play a role in troglitazone-associated carcinogenesis.
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