PT  - JOURNAL ARTICLE
AU  - Sang K. Kim
AU  - Kimberley J. Woodcroft
AU  - Sang G. Kim
AU  - Raymond F. Novak
TI  - INSULIN AND GLUCAGON SIGNALING IN REGULATION OF MICROSOMAL EPOXIDE HYDROLASE EXPRESSION IN PRIMARY CULTURED RAT HEPATOCYTES
AID  - 10.1124/dmd.31.10.1260
DP  - 2003 Oct 01
TA  - Drug Metabolism and Disposition
PG  - 1260--1268
VI  - 31
IP  - 10
4099  - http://dmd.aspetjournals.org/content/31/10/1260.short
4100  - http://dmd.aspetjournals.org/content/31/10/1260.full
SO  - Drug Metab Dispos2003 Oct 01; 31
AB  - Microsomal epoxide hydrolase (mEH) plays an important role in the detoxification of a broad range of epoxide intermediates and has been reported to be decreased during diabetes and fasting. The signaling pathways involved in the regulation of mEH expression in response to insulin and glucagon were examined in primary cultured rat hepatocytes. mEH protein levels were increased 2- to 6-fold in hepatocytes cultured for 1 to 4 days, respectively, in the presence of insulin. Concentration-response studies revealed that insulin concentrations ≥1 nM resulted in increased mEH protein levels. The phosphatidylinositol 3-kinase (PI3K) inhibitors wortmannin or LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one], and rapamycin, an inhibitor of p70 S6 kinase phosphorylation, ameliorated the insulin-mediated increase in mEH protein levels. The p38 mitogen-activated protein (MAP) kinase inhibitors SB203580 and SB202190 also abrogated the insulin-mediated increase in mEH protein. Treatment of cells with glucagon, 8-bromo-cAMP, or dibutyryl-cAMP for 3 days resulted in decreased mEH protein levels. Pretreatment with the protein kinase A (PKA) inhibitor H89 (N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline) prior to glucagon addition markedly attenuated the glucagon effect, implicating PKA signaling in the regulation of mEH expression. These data demonstrate that insulin and glucagon regulate, in an opposing manner, the expression of mEH in primary cultured rat hepatocytes. Furthermore, these data suggest that PI3K and p70 S6 kinase are active in the regulation of insulin-mediated mEH expression. We also provide data implicating p38 MAP kinase in the insulin-mediated increase in mEH levels. Moreover, cAMP and PKA are implicated in mediating the inhibitory effect of glucagon on mEH expression. The American Society for Pharmacology and Experimental Therapeutics