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So welcome back.
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Let's continue our lecture series on drug metabolism and talk about Phase I and Phase II reactions.
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So what we're going to do here is break this up into 2 parts.
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And so, Phase I metabolism, I just want you right now to associate it with the Cytochrome P 450 system and that's something we eluded to in the last lecture.
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And so, what enzymes is Phase I metabolism using? What class of enzymes?
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And so, the class of enzymes we use are called oxidases
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and what do these oxidases do?
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Well they unmask or introduce polar groups. Examples being -Os and -OHs. Hence, the term oxidases.
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And they unmask these polar groups on the drug.
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And what we're going to do in about one minute is actually draw out this reaction so you can see it and understand it
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and the name of these oxidases by enlarge, the largest family of drugs working in the you know Phase I metabolism are the cytochrome p450
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and so, we see CYP - that's where it comes from and then 450.
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Now where does the 450 come from?
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This has confused lots of people.
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Well, these are heme-containing enzymes and just a little historical tidbit, remember that heme binds oxygen
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but more than oxygen, heme binds carbon monoxide.
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And so, when heme binds and forms carbon monoxide, the maximum wavelength that it absorbs is 450 nanometers
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and that's where the name comes from but let's look at Phase I metabolism here.
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And the reason we're going to do this is so that you get it, so that you understand.
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So, we start with the drug and what we want to do now is take this drug, metabolize it
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and form a more water soluble drug.
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And I'm just going to write a drug with a star and that star means it's more water soluble.
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Well, the first thing, let's switch colors here.
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First thing I want to realize is we're using oxidases. We're trying to introduce our unmasked polar groups.
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And so, cytochrome p450 because we are heme-containing enzymes, we know they like to deal with oxygen.
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So, I'm just going to write in oxygen here.
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And so, one thing that does happen is we have this O2.
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One of these oxygens ends up binding to this drug.
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The other oxygen ends up forming H2O.
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So, let's just put in O here and I'll write the H2 and I'm being a little anal about color-coding but whatever. H2.
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So, where are we getting the hydrogens from?
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Well, the hydrogens we are getting from NADPH. NADPH.
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And hopefully, you remember NADPH. This is from Biochemistry.
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So, NADPH, we covered - well not we but you probably covered some time in the past. This is part of the pentose phosphate shunt or pathway.
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Whatever you want to call it.
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Do you remember when we were forming, when we took you know Glucose 6 Phosphate and we formed, 6 Phosphogluconate.
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Oh! Good old Biochemistry.
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Well as a by-product performed in NADPH - important concept.
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And so, NADPH actually acts as a reducing agent.
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It's a reducing agent.
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So, what do I mean when I say reducing agent?
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Who knew Biochemistry was going to come back.
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By reducing agent, it means it can reduce other molecules.
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And so, we remember oil rig, oxygen is lost of an electron. Reduction is gain oil rig.
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By being a reducing agent, it causes other molecules to get reduced to gain an electron.
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And as a result, it loses an electron.
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So, we would expect if it is a reducing agent, if it's losing an electron, it itself is getting oxidized
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and by losing an electron, at the end here we form NADPH+ (positively turned).
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The big picture here though is that we are using cytochrome p450, we have a requirement for molecular oxygen.
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One of those oxygens goes and binds to the drug. The other oxygen goes and typically forms water and the enzyme we are using here is cytochrome p450
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and that is Phase I metabolism.
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Now you can get much more detail with it but that's the big picture I think you should know.
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But, there are other non-cytochrome p450 enzymes that are in phase I reactions but they constitute the minority.
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But one of them I do think you should know is alcohol dehydrogenase.
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This breaks down alcohol and it takes alcohol. We use alcohol dehydrogenase and it forms acetylaldehide
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which is actually one of the side effect producing components of alcohol and acetylaldehide is later broken down into acetate.
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We'll cover that later.
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Now, the cytochrome p450 family has a unique way of being named.
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And so, we'll see these names 3A4 or 2D6. What do those mean?
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So, these are probably 2 of the most common cytochrome p450 enzymes
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And so, the way this naming works is 3 represents the family of drugs, the A represents the subfamily of enzyme
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and the 4, actually represents the actual isozyme - the individual isozyme.
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I think of this as a family. This is the you know grandmother. This is the mother and ths is the daughter
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and it's the individual person right here.
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So the iso 1 zyme 1 enzyme.
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and this is Phase 1 metabolism.
