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Ascorbic acid deficiency and hepatic UDP-glucuronyltransferase
1Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109.
Summary
Dietary ascorbic acid (vitamin C) deficiency reduces specific hepatic microsomal UDP-glucuronyltransferase (UDPGT) activity for p-aminophenol in guinea pigs. This suggests vitamin C influences specific UDPGT isozymes, impacting drug metabolism.
Area of Science:
- Biochemistry
- Pharmacology
- Nutritional Science
Background:
- Hepatic microsomal UDP-glucuronyltransferase (UDPGT) is crucial for detoxifying xenobiotics and endogenous compounds.
- Ascorbic acid (vitamin C) plays a role in various metabolic processes, but its specific impact on UDPGT activity is not fully understood.
- Previous studies indicated ascorbate deficiency affects hepatic cytochrome P-450 levels in guinea pigs.
Purpose of the Study:
- To investigate the effect of dietary ascorbic acid on hepatic microsomal UDPGT activity towards specific substrates.
- To determine if ascorbic acid influences specific UDPGT isozymes.
- To explore the protective role of ascorbic acid against substrate-induced enzyme inhibition.
Main Methods:
- Assessed UDPGT activity in liver microsomes from ascorbate-deficient and supplemented guinea pigs using p-aminophenol, bilirubin, and acetaminophen as substrates.
- Investigated the impact of membrane-perturbing agents (sonication, Triton X-100) and cofactors (magnesium chloride) on enzyme activity.
- Examined the in vitro protective effects of ascorbic acid, its analogs, and other antioxidants against substrate-induced enzyme inactivation.
Main Results:
- Ascorbate deficiency led to a 33% reduction in UDPGT activity towards p-aminophenol, but not bilirubin or acetaminophen.
- This reduction correlated with decreased hepatic microsomal cytochrome P-450 levels.
- Ascorbic acid and glutathione protected UDPGT from substrate-induced inactivation in vitro, maintaining linear activity.
- Membrane perturbation and magnesium chloride significantly altered UDPGT activity, with varying effects between the two dietary groups.
Conclusions:
- Dietary ascorbic acid specifically influences UDPGT isozymes involved in p-aminophenol conjugation.
- The observed reduction in UDPGT activity in ascorbate deficiency may be linked to altered cytochrome P-450 levels and membrane properties.
- Ascorbic acid and glutathione exhibit protective effects against UDPGT inactivation by excess substrate.