Variance component linkage analysis for the level of response to alcohol was significantly affected by including covariates for recent drinking and smoking behavior. Since CYP2E1 expression is inducible by alcohol and nicotine (Joshi and Tyndale, 2006), this further supports the role of CYP2E1 in level of response to alcohol. CYP2E1 represents a metabolic intersection between these substances of abuse (Schoedel and Tyndale, 2003). It was initially surprising that while an association was not found between the level of response to alcohol and copy number of CYP2E1, an association was found between nicotine use and copy number. Studies have shown that neither ethanol nor nicotine increase the level of CYP2E1 mRNA in rat hepatic tissue (Howard et al., 2001). Ethanol likely changes the activity of CYP2E1 by interacting with the active site leading to increased protein stabilization and reduced clearance by degradation. Given the induction of CYP2E1 by nicotine requires multiple doses and does not interact with the catalytic function of CYP2E1, it is thought that the mechanism behind nicotine induction is not through protein stabilization. (Micu et al., 2003; Schoedel
