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Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
FURTHER STUDIES ON THE INDUCTION OF THE DRUG-HYDROXYLATING ENZYME SYSTEM OF LIVER MICROSOMES
1Department of Pathology at Sabbatsberg Hospital, Karolinska Institutet, and The Wenner-Gren Institute, University of Stockholm, Stockholm, Sweden.
The Journal of Cell Biology
|October 30, 2009
Summary
Drug administration induces liver microsomal enzymes, with levels correlating to dosage and decreasing upon removal. This enzyme induction affects different cellular structures with repeated dosing.
Area of Science:
- Biochemistry
- Pharmacology
- Cell Biology
Background:
- Liver microsomes contain drug-hydroxylating enzymes crucial for drug metabolism.
- Enzyme induction by xenobiotics is a key adaptive response.
- Understanding the mechanisms of enzyme induction is vital for drug development and toxicology.
Purpose of the Study:
- To investigate the dose-dependent induction of liver microsomal enzymes by drugs.
- To examine the effect of inducer removal on enzyme levels.
- To determine the subcellular localization of induced enzymes and their impact on membrane synthesis.
Main Methods:
- Rats were pretreated with phenobarbital and other drugs.
- Microsomal enzyme activities (CO-binding pigment, TPNH-cytochrome c reductase, aminopyrine demethylation) were measured.
- Subcellular fractions (rough and smooth microsomes) were analyzed.
- Thin layer chromatography was used to analyze phospholipid fractions.
Main Results:
- Phenobarbital dose-proportionally increased microsomal enzymes and CO-binding pigment.
- Enzyme levels decreased in parallel with inducer removal.
- Early induction occurred in rough microsomes, shifting to smooth microsomes with repeated administration.
- Phenobarbital stimulated endoplasmic membrane formation and phospholipid synthesis.
Conclusions:
- Drug pretreatment induces liver microsomal drug-metabolizing enzymes in a dose-dependent manner.
- Enzyme synthesis is linked to endoplasmic membrane proliferation.
- Subcellular localization of induced enzymes changes with chronic drug administration.
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