Hepatic expression of cytochrome P450 in type 2 diabetic Goto-Kakizaki rats

Soo Jin Oh; Jong Min Choi; Kang Uk Yun; Jung Min Oh; Hui Chan Kwak; Jin Gyo Oh; Kye Sook Lee; Bong Hee Kim; Tae Hwe Heo; Sang Kyum Kim

doi:10.1016/j.cbi.2011.12.010

Hepatic expression of cytochrome P450 in type 2 diabetic Goto-Kakizaki rats

Soo Jin Oh, Jong Min Choi, Kang Uk Yun, Jung Min Oh, Hui Chan Kwak, Jin Gyo Oh, Kye Sook Lee, Bong Hee Kim, Tae Hwe Heo, Sang Kyum Kim

Pharmacy

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Abstract

Although hepatic expression of cytochrome P450 (CYP) changes markedly in diabetes, the role of ketone bodies in the regulation of CYP in diabetes is controversial. The present study was performed to determine the expression and activity of CYP in non-obese type II diabetic Goto-Kakizaki (GK) rats with normal levels of ketone bodies. In the present study, basal serum glucose levels increased 1.95-fold in GK rats, but acetoacetate and β-hydroxybutyrate levels were not significantly different. Hepatic expression of CYP reductase and CYP3A2 was up-regulated in the GK rats, and consequently, activities of CYP reductase and midazolam 4-hydroxylase, mainly catalyzed by CYP3A2, increased. In contrast, hepatic expression of CYP1A2 and CYP3A1 was down-regulated and the activities of 7-ethoxyresorufin-O-deethylase and 7-methoxyresorufin-O- demethylase, mainly catalyzed by CYP1A, also decreased in GK rats. Hepatic levels of microsomal protein and total CYP and hepatic expression of cytochrome b ₅, CYP1B1, CYP2B1 and CYP2C11 were not significantly different between the GK rats and normal Wistar rats. Moreover, the expression and activity of CYP2E1, reported to be up-regulated in diabetes with hyperketonemia, were not significantly different between GK rats and control rats, suggesting that elevation of ketone bodies plays a critical role in the up-regulation of hepatic CYP2E1 in diabetic rats. Our results showed that the expression of hepatic CYP is regulated in an isoform-specific manner. The present results also show that the GK rat is a useful animal model for the pathophysiological study of non-obese type II diabetes with normal ketone body levels.

Original language	English
Pages (from-to)	173-179
Number of pages	7
Journal	Chemico-Biological Interactions
Volume	195
Issue number	3
DOIs	https://doi.org/10.1016/j.cbi.2011.12.010
State	Published - 5 Feb 2012

Bibliographical note

Funding Information:
This work was supported by a Grant (No. K10050 to S.K. Kim) from the Korea Institute of Oriental Medicine (KIOM) funded by the Ministry of Education, Science and Technology (MEST) , by a Grant of the Korea Healthcare Technology R&D Project funded by the Ministry for Health, Welfare & Family Affairs, Republic of Korea ( A100096 ), and by the Research Fund 2011 of The Catholic University of Korea (T.-H. Heo).

Keywords

Cytochrome P450
Diabetes
GK rat
Hepatic metabolism
Ketone body

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cbi.2011.12.010

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title = "Hepatic expression of cytochrome P450 in type 2 diabetic Goto-Kakizaki rats",

abstract = "Although hepatic expression of cytochrome P450 (CYP) changes markedly in diabetes, the role of ketone bodies in the regulation of CYP in diabetes is controversial. The present study was performed to determine the expression and activity of CYP in non-obese type II diabetic Goto-Kakizaki (GK) rats with normal levels of ketone bodies. In the present study, basal serum glucose levels increased 1.95-fold in GK rats, but acetoacetate and β-hydroxybutyrate levels were not significantly different. Hepatic expression of CYP reductase and CYP3A2 was up-regulated in the GK rats, and consequently, activities of CYP reductase and midazolam 4-hydroxylase, mainly catalyzed by CYP3A2, increased. In contrast, hepatic expression of CYP1A2 and CYP3A1 was down-regulated and the activities of 7-ethoxyresorufin-O-deethylase and 7-methoxyresorufin-O- demethylase, mainly catalyzed by CYP1A, also decreased in GK rats. Hepatic levels of microsomal protein and total CYP and hepatic expression of cytochrome b 5, CYP1B1, CYP2B1 and CYP2C11 were not significantly different between the GK rats and normal Wistar rats. Moreover, the expression and activity of CYP2E1, reported to be up-regulated in diabetes with hyperketonemia, were not significantly different between GK rats and control rats, suggesting that elevation of ketone bodies plays a critical role in the up-regulation of hepatic CYP2E1 in diabetic rats. Our results showed that the expression of hepatic CYP is regulated in an isoform-specific manner. The present results also show that the GK rat is a useful animal model for the pathophysiological study of non-obese type II diabetes with normal ketone body levels.",

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author = "Oh, {Soo Jin} and Choi, {Jong Min} and Yun, {Kang Uk} and Oh, {Jung Min} and Kwak, {Hui Chan} and Oh, {Jin Gyo} and Lee, {Kye Sook} and Kim, {Bong Hee} and Heo, {Tae Hwe} and Kim, {Sang Kyum}",

note = "Funding Information: This work was supported by a Grant (No. K10050 to S.K. Kim) from the Korea Institute of Oriental Medicine (KIOM) funded by the Ministry of Education, Science and Technology (MEST) , by a Grant of the Korea Healthcare Technology R&D Project funded by the Ministry for Health, Welfare & Family Affairs, Republic of Korea ( A100096 ), and by the Research Fund 2011 of The Catholic University of Korea (T.-H. Heo).",

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AU - Oh, Jin Gyo

AU - Lee, Kye Sook

AU - Kim, Bong Hee

AU - Heo, Tae Hwe

AU - Kim, Sang Kyum

N1 - Funding Information: This work was supported by a Grant (No. K10050 to S.K. Kim) from the Korea Institute of Oriental Medicine (KIOM) funded by the Ministry of Education, Science and Technology (MEST) , by a Grant of the Korea Healthcare Technology R&D Project funded by the Ministry for Health, Welfare & Family Affairs, Republic of Korea ( A100096 ), and by the Research Fund 2011 of The Catholic University of Korea (T.-H. Heo).

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N2 - Although hepatic expression of cytochrome P450 (CYP) changes markedly in diabetes, the role of ketone bodies in the regulation of CYP in diabetes is controversial. The present study was performed to determine the expression and activity of CYP in non-obese type II diabetic Goto-Kakizaki (GK) rats with normal levels of ketone bodies. In the present study, basal serum glucose levels increased 1.95-fold in GK rats, but acetoacetate and β-hydroxybutyrate levels were not significantly different. Hepatic expression of CYP reductase and CYP3A2 was up-regulated in the GK rats, and consequently, activities of CYP reductase and midazolam 4-hydroxylase, mainly catalyzed by CYP3A2, increased. In contrast, hepatic expression of CYP1A2 and CYP3A1 was down-regulated and the activities of 7-ethoxyresorufin-O-deethylase and 7-methoxyresorufin-O- demethylase, mainly catalyzed by CYP1A, also decreased in GK rats. Hepatic levels of microsomal protein and total CYP and hepatic expression of cytochrome b 5, CYP1B1, CYP2B1 and CYP2C11 were not significantly different between the GK rats and normal Wistar rats. Moreover, the expression and activity of CYP2E1, reported to be up-regulated in diabetes with hyperketonemia, were not significantly different between GK rats and control rats, suggesting that elevation of ketone bodies plays a critical role in the up-regulation of hepatic CYP2E1 in diabetic rats. Our results showed that the expression of hepatic CYP is regulated in an isoform-specific manner. The present results also show that the GK rat is a useful animal model for the pathophysiological study of non-obese type II diabetes with normal ketone body levels.

AB - Although hepatic expression of cytochrome P450 (CYP) changes markedly in diabetes, the role of ketone bodies in the regulation of CYP in diabetes is controversial. The present study was performed to determine the expression and activity of CYP in non-obese type II diabetic Goto-Kakizaki (GK) rats with normal levels of ketone bodies. In the present study, basal serum glucose levels increased 1.95-fold in GK rats, but acetoacetate and β-hydroxybutyrate levels were not significantly different. Hepatic expression of CYP reductase and CYP3A2 was up-regulated in the GK rats, and consequently, activities of CYP reductase and midazolam 4-hydroxylase, mainly catalyzed by CYP3A2, increased. In contrast, hepatic expression of CYP1A2 and CYP3A1 was down-regulated and the activities of 7-ethoxyresorufin-O-deethylase and 7-methoxyresorufin-O- demethylase, mainly catalyzed by CYP1A, also decreased in GK rats. Hepatic levels of microsomal protein and total CYP and hepatic expression of cytochrome b 5, CYP1B1, CYP2B1 and CYP2C11 were not significantly different between the GK rats and normal Wistar rats. Moreover, the expression and activity of CYP2E1, reported to be up-regulated in diabetes with hyperketonemia, were not significantly different between GK rats and control rats, suggesting that elevation of ketone bodies plays a critical role in the up-regulation of hepatic CYP2E1 in diabetic rats. Our results showed that the expression of hepatic CYP is regulated in an isoform-specific manner. The present results also show that the GK rat is a useful animal model for the pathophysiological study of non-obese type II diabetes with normal ketone body levels.

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Hepatic expression of cytochrome P450 in type 2 diabetic Goto-Kakizaki rats

Abstract

Bibliographical note

Keywords

UN SDGs

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