Repeated exposure to codeine alters morphine glucuronidation by affecting UGT gene expression in the rat
Letizia Antonilli1, Lorenza De Carolis, Valentina Brusadin
1Department of Physiology and Pharmacology Vittorio Erspamer, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
European Journal of Pharmacology
|September 27, 2012
Summary
Codeine and heroin impact morphine glucuronidation differently in rats. Codeine stimulates some pathways in vivo but inhibits gene expression in vitro, while heroin shows varied effects on glucuronidation and gene expression.
Area of Science:
- Pharmacology
- Hepatology
- Drug Metabolism
Background:
- Phenanthrene opioids, like heroin and naltrexone, are known to influence morphine glucuronidation in rats.
- Understanding these interactions is crucial for comprehending opioid metabolism and potential drug-drug interactions.
Purpose of the Study:
- To investigate the differential effects of codeine and heroin on morphine glucuronidation in rat liver preparations.
- To assess the impact of these opioids on the expression of key UDP-glucuronosyltransferase (UGT) genes and glucuronic acid levels.
Main Methods:
- Ex vivo study using liver microsomal preparations from rats treated with codeine.
- In vitro study using primary rat hepatocyte cultures incubated with codeine or heroin.
- Measurement of morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) synthesis.
- Determination of UGT gene expression (UGT1A1, UGT1A6, UGT1A7, UGT2B1) and UDP-glucuronic acid (UDPGA) levels.
Main Results:
- Ex vivo: Codeine stimulated M3G formation and M6G synthesis in liver microsomes.
- In vitro: Both codeine and heroin inhibited M3G formation; heroin stimulated M6G synthesis.
- Codeine decreased UGT2B1 and tended to inhibit UGT1A1 expression; heroin increased UGT2B1 and inhibited UGT1A1 expression.
- Both opioids depleted UDPGA content in hepatocytes.
Conclusions:
- Codeine and heroin exert distinct effects on morphine glucuronidation, influencing both enzyme activity and gene expression.
- Changes in UGT gene expression profiles and co-factor availability contribute to the observed modulation of morphine metabolism.
- These findings highlight the complex interplay between opioids and their metabolic pathways in the liver.
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