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

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• 作者：Kavitha Swaminathan ; S. Mathan Kumar ; Dahn L. Clemens ; Aparajita Dey
• 关键词：ADH ; alcohol dehydrogenase ; AGE ; advanced glycated end product ; CYP2E1 ; cytochrome P4502E1 ; DCF-DA ; 2&prime ; 7&prime ; -dichlorofluorescein diacetate ; GSH ; glutathione ; MEM ; minimal essential medium ; MTT ; thiazolyl blue tetrazolium bromide ; NASH ; non-alcoho
• 刊名：Biochimica et Biophysica Acta (BBA)/General Subjects
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：1830
• 期：10
• 页码：4407-4416
• 全文大小：2036 K

文摘

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 10 ¦ÌM diallyl sulfide most effectively led to decreases in the oxidative stress and toxicity as compared with ADH inhibition with 2 mM pyrazole or the combined inhibition of ADH and CYP2E1 with 5 mM 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.