Inhibition of CYP2E1 leads to decreased advanced glycated end product formation in high glucose treated ADH and CYP2E1 over-expressing VL-17A cells.

Abstract

BACKGROUND:

In recent years, there has been a growing interest to explore the association between liver injury and diabetes. Advanced glycated end product (AGE) formation which characterizes diabetic complications is formed through hyperglycemia mediated oxidative stress and is itself a source for ROS. Further, in VL-17A cells over-expressing ADH and CYP2E1, greatly increased oxidative stress and decreased viability have been observed with high glucose exposure.

METHODS:

In VL-17A cells treated with high glucose and pretreated with the different inhibitors of ADH and CYP2E1, the changes in cell viability, oxidative stress parameters and formation of AGE, were studied.

RESULTS:

Inhibition of CYP2E1 with 10μM diallyl sulfide most effectively led to decreases in the oxidative stress and toxicity as compared with ADH inhibition with 2mM pyrazole or the combined inhibition of ADH and CYP2E1 with 5mM 4-methyl pyrazole. AGE formation was decreased in VL-17A cells when compared with HepG2 cells devoid of the enzymes. Further, AGE formation was decreased to the greatest extent with the inhibitor for CYP2E1 suggesting that high glucose inducible CYP2E1 and the consequent ROS aid AGE formation.

CONCLUSIONS:

Thus, CYP2E1 plays a pivotal role in the high glucose induced oxidative stress and toxicity in liver cells as observed through direct evidences obtained utilizing the different inhibitors for ADH and CYP2E1.

GENERAL SIGNIFICANCE:

The study demonstrates the role of CYP2E1 mediated oxidative stress in aggravating hyperglycemic insult and suggests that CYP2E1 may be a vital component of hyperglycemia mediated oxidative injury in liver.

• Authors: Kavitha Swaminathan, S Mathan Kumar, Dahn L Clemens, Aparajita Dey
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1830 Issue 10 Pg. 4407-16 (Oct 2013) ISSN: 0006-3002 [Print] Netherlands
• PMID: 23707663 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Allyl Compounds
• Cytochrome P-450 CYP2E1 Inhibitors
• Glycation End Products, Advanced
• Pyrazoles
• Reactive Oxygen Species
• Sulfides
• pyrazole
• allyl sulfide
• Alcohol Dehydrogenase
• Cytochrome P-450 CYP2E1
• Glucose

Topics

• Alcohol Dehydrogenase (antagonists & inhibitors, metabolism)
• Allyl Compounds (pharmacology)
• Cell Line
• Cytochrome P-450 CYP2E1 (metabolism)
• Cytochrome P-450 CYP2E1 Inhibitors
• Glucose (pharmacology)
• Glycation End Products, Advanced (metabolism)
• Humans
• Oxidative Stress (drug effects)
• Pyrazoles (pharmacology)
• Reactive Oxygen Species (metabolism)
• Sulfides (pharmacology)