constricted, hydrophobic access channel which may also be important for determining the enzyme's specificity towards small molecules and ω-1 hydroxylation of fatty acids. . Regulation Genetic regulation In humans, the CYP2E1 enzyme is encoded by the CYP2E1 gene. The enzyme has been identified in fetal liver, where it is posited to be the predominant ethanol-metabolizing enzyme, and may be connected to ethanol-mediated teratogenesis. In rats, within one day of birth the hepatic CYP2E1 gene is activated transcriptionally. CYP2E1 expression is easily inducible, and can occur in the presence of a number of its substrates, including ethanol, isoniazid, tobacco, isopropanol, benzene, toluene, and acetone. For ethanol specifically, it seems that there exist two stages of induction, a post-translational mechanism for increased protein stability at low levels of ethanol and an additional transcriptional induction at high levels of ethanol. Chemical regulation CYP2E1 is inhibited by a variety of small molecules, many of which act competitively. Two such inhibitors, indazole and 4-methylpyrazole, coordinate with the active site's iron atom and were crystallized with recombinant human CYP2E1 in 2008 to give the first true crystal structures of the enzyme. Other inhibitors include diethyldithiocarbamate (in cancer), and disulfiram (in alcoholism). Disease relevance CYP2E1 is expressed in high levels in the liver, where it works to clear toxins from the body. In doing so, CYP2E1 bioactivates a variety of common anesthetics, including acetaminophen, halothane, enflurane, and isoflurane. The oxidation of these molecules by CYP2E1 can produce harmful substances such as trifluoroacetic acid chloride from halothane or NAPQI from paracetamol (acetaminophen) and is a major reason for their observed hepatotoxicity in patients. CYP2E1 and other cytochrome P450 enzymes can inadvertently produce reactive oxygen species (ROS) in their active site when catalysis is not coordinated correctly, resulting in potential lipid peroxidation as well as protein and DNA oxidation. CYP2E1 is particularly susceptible to this phenomenon compared to other P450 enzymes, suggesting that its expression levels may be important for negative physiological effects observed in a number of disease states. CYP2E1 expression levels have been correlated with a variety of dietary and physiological factors, such as ethanol consumption, diabetes, fasting, and obesity. It appears that cellular levels of the enzyme may be controlled by the molecular chaperone HSP90, which upon association with CYP2E1 allows for transport to the proteasome and subsequent degradation. Ethanol and other substrates may disrupt this association, leading to the higher expression levels observed in their