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Cytochrome P450

  1. Jun 20, 2008 #1
    Does anyone have any background about this gene, CYP?
    It's been around for years now, but I'm really confuse as to what this actually does.
    I've been doing some research and different websites tell me different thing, some that contradicts with each other.
    For example, Cytochrome P450 1A1 or CYP1A1, is suppose to metabolize Xenobiotics(toxins),
    but then other websites tell me that it produces benzo pyrene, the Ultimate Carcinogen.
    I know the entire superfamily of CYP is used to metabolize toxins and fats, so does this one gene actually hurt us? Maybe it's my definition of metabolism, which in this context I believe it means to break down the toxin. So is it possible that by breaking down the toxin, our bodies are actually producing an even more dangerous carcinogen?
     
  2. jcsd
  3. Jun 21, 2008 #2
    Cytochromes P450 are a very large and diverse superfamily of proteins that perform a wide range of bio-oxidations. Their roles in humans range from lipid and steroid biosynthesis to drug metabolism to xenobiotic clearance. There are a number of isoforms (for example, you have CYP1A1, CYP2B4, CYP2C5, CYP2C8, CYP2C9, CYP2D6, CYP3A4, and so on) of the same basic protein core. Various isoforms can be differentially expressed in different tissues/organs, so it's certainly possible that in, for instance, the liver an isoform does primarily reaction A while it does reaction B primarily in the intestines. So it is quite understandable that a single isoform can certainly do both things - essential metabolism as well as metabolism of xenobiotic substances. Cytochromes P450 are well known for having some degree of substrate promiscuity and plasticity, although this can vary from isoform to isoform. For instance, the 3A4 isoform is known to have a very large and very flexible active site, able to handle processing large natural products with ease, while the 2A6 isoform has a smaller and more compact active site which handles small, planar molecules efficiently.

    Having said that, CYP1A1 is inducible by benzopyrene, where benzopyrene binds to a receptor that regulates production of CYP1A1 - basically, when that happens, the increased concentration of CYP1A1 helps to clear benzopyrene from the environment, making the benzopyrene byproduct more reactive, but also making it more soluble so it can be more easily excreted. (It does not produce benzopyrene, though. Where did you find that? I'd be interested in seeing that argument, it sounds rather dubious to me.) It's a double-edged sword. It's for reasons like this that, sometimes, when one is prescribed drugs, one has to be careful about drug-drug interactions. This can include both prescription drugs and natural products (occasionally it is noted that one shouldn't take certain drugs with fluids like grapefruit juice). The interaction of various drugs with one another, or with naturally occurring chemicals can screw up the expected pharmacokinetics and clearance, which can lead to a buildup of reactive byproducts.

    CYPs aren't dangerous, they're essential. They're found in practically every organism out there, from bacteria to plants to mammals. It can seem counter-intuitive and contradictory, but they are a ubiquitous enzyme family that does a wide range of oxidative chemistry in a variety of contexts. I hope this clears up your question.
     
    Last edited: Jun 21, 2008
  4. Jun 21, 2008 #3
    So
    1)CYPs are good, necessary for removing xenobiotics.
    2)They don't make toxins, just (could)activates those that are already in the body, such as those that has entered through drinking and smoking and make them more reactive, making this into a double edge sword type of situation.

    So it is safe unless triggered through like you said drug to drug interaction.
    This one website stated that

    "CYP enzymes are, however, also central for the metabolic activation of foreign compounds into reactive, toxic metabolites. This process is called bioactivation. Drugs and chemicals can be bioactivated to reactive metabolites capable of binding irreversibly to proteins and DNA. The binding of reactive metabolites to vital macromolecules is often regarded as an initial event triggering a cascade of biochemical changes and cell death."

    This implies that they want the cell to die on purpose right? Is it to prevent it from becoming a cancer cell when it divides since the toxin has damaged the cell?

    http://www.medfarm.uu.se/forskning/program.php?vetenskapsid=2&forskomr=45&id=230&lang=en
     
    Last edited: Jun 21, 2008
  5. Jun 21, 2008 #4
    Well, they do produce byproducts from foreign substances which are toxins, but they're not responsible for the formation of those foreign substances in the first place (insofar as memory serves). Those foreign substances are what you inhale, absorb through the skin, eat, and otherwise intake into your body.

    One way for the production of these toxic byproducts is through unwanted interactions with drugs or other natural products. But it's not the only way. Some of it will naturally occur, which I will explain more in the example I give below.

    I wouldn't ascribe anthropomorphic notions such as "they want the cell to die on purpose" to cytochromes P450. :wink: Certainly, cytochromes P450 have been implicated in apoptosis (programmed cell death), which is a natural and even desirable process, although I'm not overly familiar with too much of the literature in this particular area of P450 research. But yes, if a cell is exposed to various toxins, it's better to kill off the cell through an apoptotic pathway than let it become malignant.

    Let me provide a hypothetical example that may be a useful means of thinking about this issue. There is a minimal level of expression of the various P450 isoforms in your cells. The exact amounts can vary between the different organs/tissues (liver, intestine, brain, heart, eye, and the rest). Statistically, you may have some unwanted byproducts, but the cell's machinery to protect against these byproducts (metabolites, reactive oxygen species, whatever) is more than adequate to handle what pops out on occasion. It's not intentional or part of a scheme to kill off the cell - sometimes you have a substrate dock into the protein, electrons and water show up, and you spit out an unwanted, highly toxic byproduct. But for the most part, it's at such a low level it doesn't register.

    However, let's say that you get exposed to some nasty foreign compounds. This throws off the default regulation of P450 production in your cells as a response to the toxins. So under normal circumstances, for example, in your intestine you make a certain amount of each isoform, in your brain you make a certain amount of each, and so on. With the toxin floating around in high concentrations, the P450 expression "matrix" goes out of balance. The result is the production of these reactive toxic byproducts. This throws your cellular metabolism out of whack and the naturally occurring protection mechanisms in your cells can't keep up. Thus, the cell ultimately dies from activation of the apoptotic pathway.

    Pretty much all P450 chemistry is simply oxidation of an unreactive molecule (typically inserting a single oxygen atom into carbon-hydrogen bond to form an alcohol). This sort of chemistry is ubiquitous and can flip between wanted and unwanted very easily.
     
  6. Jun 22, 2008 #5
    Thanks for clearing up my confusion.
    I really appreciate it and the amount of effort you put in your responses.
    ^_^
     
  7. Jun 22, 2008 #6
    You're welcome. The CYP superfamily is incredibly diverse, there are always the occasional odd exemption and there are frequently multiple pathways in which the P450 enzymes can find themselves enmeshed. It's important to keep that in mind - it's not that there's something wrong in your understanding, it's just that it's a lot more complicated than can be expressed in two short replies.

    Anyway. If you're really curious about more, I would recommend looking up past P450 conferences and symposia to find speakers who are doing work in the areas that interest you. Yes, that means there are conferences and symposia dedicated to *just* P450s, that's how much is out there.
     
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