CYP2E1

Cytochrome P450 2E1 (abbreviated CYP2E1, EC 1.14.13.n7) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, including CYP1, CYP2, and CYP3, which as a group are largely responsible for the breakdown of foreign compounds in mammals.^[5]

While CYP2E1 itself carries out a relatively low number of these reactions (~4% of known P450-mediated drug oxidations), it and related enzymes CYP1A2 and CYP3A4 are responsible for the breakdown of many toxic environmental chemicals and carcinogens that enter the body, in addition to basic metabolic reactions such as fatty acid oxidations.^[6]

CYP2E1 protein localizes to the endoplasmic reticulum and is induced by ethanol, the diabetic state, and starvation. The enzyme metabolizes both endogenous substrates, such as ethanol, acetone, and acetal, as well as exogenous substrates including benzene, carbon tetrachloride, ethylene glycol, and nitrosamines which are premutagens found in cigarette smoke. Due to its many substrates, this enzyme may be involved in such varied processes as gluconeogenesis, hepatic cirrhosis, diabetes, and cancer.^[7]

Function

CYP2E1 is a membrane protein expressed in high levels in the liver, where it composes nearly 50% of the total hepatic cytochrome P450 mRNA^[8] and 7% of the hepatic cytochrome P450 protein.^[9] The liver is therefore where most drugs undergo deactivation by CYP2E1, either directly or by facilitated excretion from the body.

CYP2E1 enzyme metabolizes mostly small, polar molecules, including toxic laboratory chemicals such as

CYP2E1 exhibits structural motifs common to other human membrane-bound cytochrome P450 enzymes, and is composed of 12 major α-helices and 4 β-sheets with short intervening helices interspersed between the two.^[14] Like other enzymes of this class, the active site of CYP2E1 contains an iron atom bound by a heme center which mediates the electron transfer steps necessary to carry out oxidation of its substrates. The active site of CYP2E1 is the smallest observed in human P450 enzymes, with its small capacity attributed in part to the introduction of an isoleucine at position 115. The side-chain of this residue protrudes out above the heme center, restricting active site volume compared to related enzymes that have less bulky residues at this position.^[14] T³⁰³, which also protrudes into the active site, is particularly important for substrate positioning above the reactive iron center and is hence highly conserved by many cytochrome P450 enzymes.^[14] Its hydroxyl group is well-positioned to donate a hydrogen bond to potential acceptors on the substrate, and its methyl group has also been implicated in the positioning of fatty acids within the active site.^[25],[26] A number of residues proximal to the active site including L³⁶⁸ help make up a 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.^[14]

.

Regulation

Genetic regulation

In humans, the CYP2E1 enzyme is encoded by the CYP2E1

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.^[14] 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.^[14]

CYP2E1 expression levels have been correlated with a variety of dietary and physiological factors, such as ethanol consumption,^[32] diabetes,^[33] fasting,^[34] and obesity.^[35] 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 presence.^[36] The increased expression of CYP2E1 accompanying these health conditions may therefore contribute to their pathogenesis by increasing the rate of production of ROS in the body.^[14]

According to a 1995 publication by Y Hu et al., a study in rats revealed a 8- to 9-fold elevation of CYP2E1 with fasting alone, compared to a 20-fold increase in enzyme level accompanied by a 16-fold increase in total catalytic capacity in rats who were both fasted and given large quantities of ethanol for 3 consecutive days. Starvation appears to upregulate CYP2E1 mRNA production in liver cells while alcohol seems to stabilize the enzyme itself post-translation and thus protect it from degradation by normal cellular proteolytic processes, giving the two an independent synergistic effect.

Applications

Trees have been genetically engineered to overexpress rabbit CYP2E1 enzyme. These

• Cytochrome
• Metabolism
• List of cytochrome P450 modulators

References