Submitted to: Society of Toxicology
Publication Type: Abstract Only
Publication Acceptance Date: 9/30/2002
Publication Date: 3/15/2003
Citation: BADGER, T.M., RONIS, M., CHEN, Y., HE, L. EFFECTS OF CHRONIC ETHANOL ON HEPATIC CYP2C11 IN MALE RATS: INTERACTIONS WITH THE JAK2-STAT5B PATHWAY.. SOCIETY OF TOXICOLOGY. 2003. v. 72(S1). p.110. Abstract No. 537. Interpretive Summary: Alcohol has long been known to stunt growth. At least part of this effect is associated with disruption of the hormonal system that controls growth (i.e., the growth hormone /IGF-1 system). Chronic ethanol intake alters growth hormone (GH) in the blood, and this could explain reduced growth. However, it is also possible that ethanol disrupts GH actions on cells. The pattern of GH levels in the blood differs between male and female rats. One cellular pathway stimulated by these sexually dimorphic patterns of blood GH is the JAK-STAT pathway. This pathway regulates sex-specific expression of a number of liver enzymes in the rat, including the male-specific cytochrome P450 enzyme, CYP2C11. In the current study we showed that chronic ethanol significantly reduced the levels of CYP2C11 in male rat liver. In addition, ethanol reduced levels of another important protein in GH action, STAT5b. This demonstrates that ethanol does disrupt the JAK-STAT5b pathway that is important in GH actions. Ethanol has these effects by altering gene regulation. Thus, ethanol intake can alter GH patterns in the blood and alter the actions of GH at cells. We are now studying the effects of diet on growth hormone regulation by ethanol.
Technical Abstract: Chronic alcohol consumption results in altered expression of many genes. These effects are often secondary to alterations in hormonal actions. GH is secreted from the pituitary gland in a sexually dimorphic pulsatile pattern and this secretory pattern is known to be important in the regulation of gene expression involving the JAK-STAT signal transduction pathway. Chronic alcohol treatment in male rats results in: 1) demasculinization of the GH pulse pattern; and 2) decreased expression of the male-predominant hepatic CYP2C11. Using the total enteral nutrition (TEN) model, Western and Northern analysis and electrophoretic mobility shift assays, we have evaluated the involvement of the JAK-STAT pathway in male rats (8-10/group) chronically infused intragastric diets with or without ethanol for 45 days. We have found that hepatic levels of CYP2C11 mRNA and protein, STAT 5b and phospho-STAT 5b levels were reduced (P less than/equal to 0.05) in ethanol-infused rats as compared to rats not infused with ethanol. However, the levels of JAK2 were elevated (P less than/equal to 0.05) in ethanol-treated rats. These results suggest that: 1) the JAK2 suppression in the classic GHR-JAK-STAT-CYP2C11 pathway is masked by ethanol-induced increases in other JAK2-dependent pathways; or 2) ethanol does not reduce CYP2C11 through the Classical GH-GHR-JAK2-STAT5b pathway.