Xenobiotic

A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compounds can also become xenobiotics if they are taken up by another organism, such as the uptake of natural human hormones by fish found downstream of sewage treatment plant outfalls, or the chemical defenses produced by some organisms as protection against predators.^[1] The term xenobiotic is also used to refer to organs transplanted from one species to another.

The term xenobiotics, however, is very often used in the context of pollutants such as dioxins and polychlorinated biphenyls and their effect on the biota, because xenobiotics are understood as substances foreign to an entire biological system, i.e. artificial substances, which did not exist in nature before their synthesis by humans. The term xenobiotic is derived from the Greek words ξένος (xenos) = foreigner, stranger and βίος (bios) = life, plus the Greek suffix for adjectives -τικός, -ή, -όν (-tikos, -ē, -on). Xenobiotics may be grouped as carcinogens, drugs, environmental pollutants, food additives, hydrocarbons, and pesticides.

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So welcome back. Let's continue our lecture series on drug metabolism and talk about Phase I and Phase II reactions. So what we're going to do here is break this up into 2 parts. 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. And so, what enzymes is Phase I metabolism using? What class of enzymes? And so, the class of enzymes we use are called oxidases and what do these oxidases do? Well they unmask or introduce polar groups. Examples being -Os and -OHs. Hence, the term oxidases. And they unmask these polar groups on the drug. 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 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 and so, we see CYP - that's where it comes from and then 450. Now where does the 450 come from? This has confused lots of people. Well, these are heme-containing enzymes and just a little historical tidbit, remember that heme binds oxygen but more than oxygen, heme binds carbon monoxide. And so, when heme binds and forms carbon monoxide, the maximum wavelength that it absorbs is 450 nanometers and that's where the name comes from but let's look at Phase I metabolism here. And the reason we're going to do this is so that you get it, so that you understand. So, we start with the drug and what we want to do now is take this drug, metabolize it and form a more water soluble drug. And I'm just going to write a drug with a star and that star means it's more water soluble. Well, the first thing, let's switch colors here. First thing I want to realize is we're using oxidases. We're trying to introduce our unmasked polar groups. And so, cytochrome p450 because we are heme-containing enzymes, we know they like to deal with oxygen. So, I'm just going to write in oxygen here. And so, one thing that does happen is we have this O2. One of these oxygens ends up binding to this drug. The other oxygen ends up forming H2O. 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. So, where are we getting the hydrogens from? Well, the hydrogens we are getting from NADPH. NADPH. And hopefully, you remember NADPH. This is from Biochemistry. 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. Whatever you want to call it. Do you remember when we were forming, when we took you know Glucose 6 Phosphate and we formed, 6 Phosphogluconate. Oh! Good old Biochemistry. Well as a by-product performed in NADPH - important concept. And so, NADPH actually acts as a reducing agent. It's a reducing agent. So, what do I mean when I say reducing agent? Who knew Biochemistry was going to come back. By reducing agent, it means it can reduce other molecules. And so, we remember oil rig, oxygen is lost of an electron. Reduction is gain oil rig. By being a reducing agent, it causes other molecules to get reduced to gain an electron. And as a result, it loses an electron. So, we would expect if it is a reducing agent, if it's losing an electron, it itself is getting oxidized and by losing an electron, at the end here we form NADPH+ (positively turned). The big picture here though is that we are using cytochrome p450, we have a requirement for molecular oxygen. 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 and that is Phase I metabolism. Now you can get much more detail with it but that's the big picture I think you should know. But, there are other non-cytochrome p450 enzymes that are in phase I reactions but they constitute the minority. But one of them I do think you should know is alcohol dehydrogenase. This breaks down alcohol and it takes alcohol. We use alcohol dehydrogenase and it forms acetylaldehide which is actually one of the side effect producing components of alcohol and acetylaldehide is later broken down into acetate. We'll cover that later. Now, the cytochrome p450 family has a unique way of being named. And so, we'll see these names 3A4 or 2D6. What do those mean? So, these are probably 2 of the most common cytochrome p450 enzymes And so, the way this naming works is 3 represents the family of drugs, the A represents the subfamily of enzyme and the 4, actually represents the actual isozyme - the individual isozyme. I think of this as a family. This is the you know grandmother. This is the mother and ths is the daughter and it's the individual person right here. So the iso 1 zyme 1 enzyme. and this is Phase 1 metabolism.

Xenobiotic metabolism

The body removes xenobiotics by xenobiotic metabolism. This consists of the deactivation and the excretion of xenobiotics and happens mostly in the liver. Excretion routes are urine, feces, breath, and sweat. Hepatic enzymes are responsible for the metabolism of xenobiotics by first activating them (oxidation, reduction, hydrolysis, and/or hydration of the xenobiotic), and then conjugating the active secondary metabolite with glucuronic acid, sulfuric acid, or glutathione, followed by excretion in bile or urine. An example of a group of enzymes involved in xenobiotic metabolism is hepatic microsomal cytochrome P450. These enzymes that metabolize xenobiotics are very important for the pharmaceutical industry because they are responsible for the breakdown of medications. A species with this unique cytochrome P450 system is Drosophila mettleri, which uses xenobiotic resistance to exploit a wider nesting range including both soil moistened with necrotic exudates and necrotic plots themselves.

Although the body is able to remove xenobiotics by reducing it to a less toxic form through xenobiotic metabolism then excreting it, it is also possible for it to be converted into a more toxic form in some cases. This process is referred to as bioactivation and can result in structural and functional changes to the microbiota.^[2] Exposure to xenobiotics can disrupt the microbiome community structure, either by increasing or decreasing the size of certain bacterial populations depending on the substance. Functional changes that result vary depending on the substance and can include increased expression in genes involved in stress response and antibiotic resistance, changes in the levels of metabolites produced, etc.^[3]

Organisms can also evolve to tolerate xenobiotics. An example is the co-evolution of the production of tetrodotoxin in the rough-skinned newt and the evolution of tetrodotoxin resistance in its predator, the Common Garter Snake. In this predator–prey pair, an evolutionary arms race has produced high levels of toxin in the newt and correspondingly high levels of resistance in the snake.^[4] This evolutionary response is based on the snake evolving modified forms of the ion channels that the toxin acts upon, so becoming resistant to its effects.^[5] Another example of a xenobiotic tolerance mechanism is the use of ATP-binding cassette (ABC) transporters, which is largely exhibited in insects.^[6] Such transporters contribute to resistance by enabling the transport of toxins across the cell membrane, thus preventing accumulation of these substances within cells.

Xenobiotics in the environment

Xenobiotic substances are an issue for sewage treatment systems, since they are many in number, and each will present its own problems as to how to remove them (and whether it is worth trying to)

Some xenobiotics substances are resistant to degradation. Xenobiotics such as polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs), and trichloroethylene (TCE) accumulate in the environment due to their recalcitrant properties and have become an environmental concern due to their toxicity and accumulation. This occurs particularly in the subsurface environment and water sources, as well as in biological systems, having the potential to impact human health.^[7] Some of the main sources of pollution and the introduction of xenobiotics into the environment come from large industries such as pharmaceuticals, fossil fuels, pulp and paper bleaching and agriculture.^[8] For example, they may be synthetic organochlorides such as plastics and pesticides, or naturally occurring organic chemicals such as polyaromatic hydrocarbons (PAHs) and some fractions of crude oil and coal.

Microorganisms may be a viable solution to this issue of environmental pollution by the degradation of the xenobiotics; a process known as bioremediation.^[9] Microorganisms are able to adapt to xenobiotics introduced into the environment through horizontal gene transfer, in order to make use of such compounds as energy sources.^[8] This process can be further altered to manipulate the metabolic pathways of microorganisms in order to degrade harmful xenobiotics under specific environmental conditions at a more desirable rate.^[8] Mechanisms of bioremediation include both genetically engineering microorganisms and isolating the naturally occurring xenobiotic degrading microbes.^[9] Research has been conducted to identify the genes responsible for the ability of microorganisms to metabolize certain xenobiotics and it has been suggested that this research can be used in order to engineer microorganisms specifically for this purpose.^[9] Not only can current pathways be engineered to be expressed in other organisms, but the creation of novel pathways is a possible approach.^[8]

Xenobiotics may be limited in the environment and difficult to access in areas such as the subsurface environment.^[8] Degradative organisms can be engineered to increase mobility in order to access these compounds, including enhanced chemotaxis.^[8] One limitation of the bioremediation process is that optimal conditions are required for proper metabolic functioning of certain microorganisms, which may be difficult to meet in an environmental setting.^[7] In some cases a single microorganism may not be capable of performing all metabolic processes required for degradation of a xenobiotic compound and so "syntrophic bacterial consortia" may be employed.^[8] In this case, a group of bacteria work in conjunction, resulting in dead end products from one organism being further degraded by another organism.^[7] In other cases, the products of one microorganisms may inhibit the activity another, and thus a balance must be maintained.^[8]

Many xenobiotics produce a variety of biological effects, which is used when they are characterized using bioassay. Before they can be registered for sale in most countries, xenobiotic pesticides must undergo extensive evaluation for risk factors, such as toxicity to humans, ecotoxicity, or persistence in the environment. For example, during the registration process, the herbicide, cloransulam-methyl was found to degrade relatively quickly in soil.^[10]

Inter-species organ transplantation

The term xenobiotic is also used to refer to organs transplanted from one species to another. For example, some researchers hope that hearts and other organs could be transplanted from pigs to humans. Many people die every year whose lives could have been saved if a critical organ had been available for transplant. Kidneys are currently the most commonly transplanted organ. Xenobiotic organs would need to be developed in such a way that they would not be rejected by the immune system.

References

^ Mansuy D (2013). "Metabolism of xenobiotics: beneficial and adverse effects". Biol Aujourdhui. 207 (1): 33–37. doi:10.1051/jbio/2013003. PMID 23694723. S2CID 196540867.
^ Park, B.K.; Laverty, H.; Srivastava, A.; Antoine, D.J.; Naisbitt, D.; Williams, D.P. (2011). "Drug bioactivation and protein adduct formation in the pathogenesis of drug-induced toxicity". Chemico-Biological Interactions. 192 (1–2): 30–36. doi:10.1016/j.cbi.2010.09.011. PMID 20846520.
^ Lu, Kun; Mahbub, Ridwan; Fox, James G. (31 August 2015). "Xenobiotics: Interaction with the Intestinal Microflora". ILAR Journal. 56 (2): 218–227. doi:10.1093/ilar/ilv018. ISSN 1084-2020. PMC 4654756. PMID 26323631.
^ Brodie ED, Ridenhour BJ, Brodie ED (2002). "The evolutionary response of predators to dangerous prey: hotspots and coldspots in the geographic mosaic of coevolution between garter snakes and newts". Evolution. 56 (10): 2067–82. doi:10.1554/0014-3820(2002)056[2067:teropt]2.0.co;2. PMID 12449493.
^ Geffeney S, Brodie ED, Ruben PC, Brodie ED (2002). "Mechanisms of adaptation in a predator–prey arms race: TTX-resistant sodium channels". Science. 297 (5585): 1336–9. Bibcode:2002Sci...297.1336G. doi:10.1126/science.1074310. PMID 12193784. S2CID 8816337.
^ Broehan, Gunnar; Kroeger, Tobias; Lorenzen, Marcé; Merzendorfer, Hans (16 January 2013). "Functional analysis of the ATP-binding cassette (ABC) transporter gene family of Tribolium castaneum". BMC Genomics. 14: 6. doi:10.1186/1471-2164-14-6. ISSN 1471-2164. PMC 3560195. PMID 23324493.
^ ^a ^b ^c Biodegradation and bioremediation. Singh, Ajay, 1963-, Ward, Owen P., 1947-. Berlin: Springer. 2004. ISBN 978-3540211013. OCLC 54529445.{{cite book}}: CS1 maint: others (link)
^ ^a ^b ^c ^d ^e ^f ^g ^h Díaz, Eduardo (September 2004). "Bacterial degradation of aromatic pollutants: a paradigm of metabolic versatility". International Microbiology. 7 (3): 173–180. ISSN 1139-6709. PMID 15492931.
^ ^a ^b ^c Singleton, Ian (January 1994). "Microbial metabolism of xenobiotics: Fundamental and applied research". Journal of Chemical Technology and Biotechnology. 59 (1): 9–23. doi:10.1002/jctb.280590104.
^ Wolt JD, Smith JK, Sims JK, Duebelbeis DO (1996). "Products and kinetics of cloransulam-methyl aerobic soil metabolism". J. Agric. Food Chem. 44: 324–332. doi:10.1021/jf9503570.{{cite journal}}: CS1 maint: multiple names: authors list (link)

This page was last edited on 13 December 2023, at 07:40

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