With increasing blood alcohol concentration, a secondary pathway for ethanol metabolism kicks in using the microsomal cytochrome P450 enzyme CYP2E1 (7). When the ethanol concentration is low, CYP2E1 is only responsible for oxidizing around 10% of the ethanol, but as the blood alcohol concentration increases, so does the activity of CYP2E1 in metabolizing ethanol. Chronic alcohol consumption increases the CYP2E1 levels, which allow the enzyme to play a larger role in ethanol metabolism in chronic alcoholics. In addition to the oxidation of ethanol, CYP2E1 also oxidizes a variety of substrates including certain drugs (3).
Figure 8: Three proposed pathways for the oxidation of ethanol to acetaldehyde by cytochrome P450 2E1.
There are three proposed mechanisms for ethanol oxidation by CYP2E1, all utilizing radical chemistry, as shown in the scheme above. The first mechanism is initiated by a hydrogen abstraction from the alpha carbon of ethanol, followed by the rebound of oxygen, forming a gem-diol intermediate which is then dehydrated to produce acetaldehyde and regenerate the gem-diol. The second mechanism is characterized by a dual-hydrogen abstraction, in which the first hydrogen is abstracted from the alpha carbon of ethanol, and then another hydrogen is abstracted from the oxygen in the hydroxyl group of ethanoyl radical, bypassing the formation of the gem-diol intermediate and directly producing acetaldehyde (8). These two mechanisms beginning with the hydrogen abstraction from the alpha carbon of ethanol are proposed in multiple papers throughout the past 20 years, thus they are heavily supported in the primary literature (9). After discovering that the CYP2E1 active site is sterically unhindered above the iron center, Wang et al. proposed a new, third mechanism which they appropriately named a reversed dual-hydrogen abstraction. In this mechanism, the first hydrogen is abstracted from the oxygen of ethanol, followed by a second hydrogen abstraction from the alpha carbon of ethanol to produce acetaldehyde (8).
Figure 9: The active site of CYP2E1. Ala299 and Thr303 function as the active residues, while the blue residues form the binding pocket (pbd file: 3e6i).
Wang et al. determined that the reverse dual-hydrogen abstraction (R-DHA) mechanism is predominant in polar environments, while in nonpolar environments the oxidation of ethanol is carried out competitively through the gem-diol mechanism and the R-DHA mechanism. This conclusion led Wang et al. to propose an argument for how CYP2E1 is able to adapt a significant role in ethanol oxidation when the blood ethanol concentration is high. The discovery that ethanol is a modulator of CYP2E1 substrate metabolism, signifying that ethanol oxidation by CYP2E1 can be induced by ethanol, was the key event that allowed Wang et al. to be able to explain this adaptive role of CYP2E1 (8).
When blood ethanol concentration is low, there is only a small amount of ethanol in the heme pocket, contributing to a small bulk polarity which causes the competition between the gem-diol and R-DHA mechanisms to occur. When blood ethanol concentration rises, more and more ethanol molecules enter the heme pocket, increasing the bulk polarity, allowing the R-DHA mechanism to become the primary mechanism through which ethanol oxidation occurs which in turn causes the rate of ethanol metabolism by CYP2E1 to increase as the competitive factor is eliminated (8).
November 7, 2016 at 7:32 pm
Could you make your figures a little bit larger? On my screen they show up quite small and the small text is a little difficult to read.
I think Figure 11 is a good view of the active site. You say Ala299 and Thr303 are the active residues; could you explain somewhere how?
November 10, 2016 at 4:20 pm
The text is pretty small in Figure 10, enlarging that figure might be beneficial.
On your Answer page, I mentioned wanting differences between cytochrome P450, catalase, and ADH, which you have shown me here, perhaps rendering the inclusion of more details about their differences on the Answer page unnecessary. However, the issue with alcohol’s effect in conjunction with other drugs remains, as in the end of the first paragraph here you briefly mention that CYP2E1 can also oxidize a variety of substrates including certain drugs. This is a cool fact, and should remain on this page, but it does manifest some discontinuity between this page and the Answer page.
November 10, 2016 at 4:23 pm
I guess the discontinuity is really between the question, answer and this page. Not just this page and the answer page. If the question page didn’t include that second question, there wouldn’t be any discontinuity.