Xenobiotic metabolism
Encyclopedia
Xenobiotic metabolism is the set of metabolic pathway
s that modify the chemical structure of xenobiotic
s, which are compounds foreign to an organism's normal biochemistry, such as drugs and poisons. These pathways are a form of biotransformation
present in all major groups of organisms, and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds; however, in some cases, the intermediates in xenobiotic metabolism can themselves be the cause of toxic effects.
Xenobiotic metabolism is divided into three phases. In phase I, enzymes such as cytochrome P450 oxidase
s introduce reactive or polar groups into xenobiotics. These modified compounds are then conjugated to polar compounds in phase II reactions. These reactions are catalysed by transferase
enzymes such as glutathione S-transferase
s. Finally, in phase III, the conjugated xenobiotics may be further processed, before being recognised by efflux transporters
and pumped out of cells.
The reactions in these pathways are of particular interest in medicine
as part of drug metabolism
and as a factor contributing to multidrug resistance
in infectious disease
s and cancer
chemotherapy
. The actions of some drugs as substrates or inhibitors
of enzymes involved in xenobiotic metabolism are a common reason for hazardous drug interaction
s. These pathways are also important in environmental science
, with the xenobiotic metabolism of microorganism
s determining whether a pollutant will be broken down during bioremediation
, or persist
in the environment. The enzymes of xenobiotic metabolism, particularly the glutathione S-transferase
s are also important in agriculture, since they may produce resistance to pesticide
s and herbicide
s.
. The solution that has evolved to address this problem is an elegant combination of physical barriers and low-specificity enzymatic
systems.
All organisms use cell membrane
s as hydrophobic permeability barriers to control access to their internal environment. Polar compounds cannot diffuse across these cell membrane
s, and the uptake of useful molecules is mediated through transport protein
s that specifically select substrates from the extracellular mixture. This selective uptake means that most hydrophilic
molecules cannot enter cells, since they are not recognised by any specific transporters. In contrast, the diffusion of hydrophobic
compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude lipid
-soluble xenobiotics using membrane barriers.
However, the existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics. These systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolise almost any non-polar compound. Useful metabolites are excluded since they are polar, and in general contain one or more charged groups.
The detoxification of the reactive by-products of normal metabolism cannot be achieved by the systems outlined above, because these species are derived from normal cellular constituents and usually share their polar characteristics. However, since these compounds are few in number, specific enzymes can recognize and remove them. Examples of these specific detoxification systems are the glyoxalase system
, which removes the reactive aldehyde
methylglyoxal, and the various antioxidant systems that eliminate reactive oxygen species.
(GSH), sulfate
, glycine
, or glucuronic acid
. These reactions are catalysed by a large group of broad-specificity transferases, which in combination can metabolise almost any hydrophobic compound that contains nucleophilic or electrophilic groups. One of the most important of these groups are the glutathione S-transferase
s (GSTs). The addition of large anionic groups (such as GSH) detoxifies reactive electrophile
s and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported.
and glycine
residues in the glutathione molecule are removed by Gamma-glutamyl transpeptidase and dipeptidase
s. In the final step, the cystine
residue in the conjugate is acetylated.
Conjugates and their metabolites can be excreted from cells in phase III of their metabolism, with the anionic groups acting as affinity tags for a variety of membrane transporters of the multidrug resistance protein
(MRP) family. These proteins are members of the family of ATP-binding cassette transporters and can catalyse the ATP-dependent transport of a huge variety of hydrophobic anions, and thus act to remove phase II products to the extracellular medium, where they may be further metabolised or excreted.
s and reactive aldehyde
s often cannot be achieved by the system described above. This is the result of these species' being derived from normal cellular constituents and usually sharing their polar characteristics. However, since these compounds are few in number, it is possible for enzymatic systems to utilize specific molecular recognition to recognize and remove them. The similarity of these molecules to useful metabolites therefore means that different detoxification enzymes are usually required for the metabolism of each group of endogenous toxins. Examples of these specific detoxification systems are the glyoxalase system
, which acts to dispose of the reactive aldehyde methylglyoxal
, and the various antioxidant
systems that remove reactive oxygen species
.
could be oxidized and conjugated to amino acids in the human body. During the remainder of the nineteenth century, several other basic detoxification reactions were discovered, such as methylation
, acetylation
, and sulfonation
.
In the early twentieth century, work moved on to the investigation of the enzymes and pathways that were responsible for the production of these metabolites. This field became defined as a separate area of study with the publication by Richard Williams
of the book Detoxication mechanisms in 1947. This modern biochemical research resulted in the identification of glutathione S-transferases in 1961, followed by the discovery of cytochrome P450s in 1962, and the realization of their central role in xenobiotic metabolism in 1963.
Drug metabolism
Microbial biodegradation
History
Metabolic pathway
In biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...
s that modify the chemical structure of xenobiotic
Xenobiotic
A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual...
s, which are compounds foreign to an organism's normal biochemistry, such as drugs and poisons. These pathways are a form of biotransformation
Biotransformation
Biotransformation is the chemical modification made by an organism on a chemical compound. If this modification ends in mineral compounds like CO2, NH4+, or H2O, the biotransformation is called mineralisation....
present in all major groups of organisms, and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds; however, in some cases, the intermediates in xenobiotic metabolism can themselves be the cause of toxic effects.
Xenobiotic metabolism is divided into three phases. In phase I, enzymes such as cytochrome P450 oxidase
Cytochrome P450 oxidase
The cytochrome P450 superfamily is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances...
s introduce reactive or polar groups into xenobiotics. These modified compounds are then conjugated to polar compounds in phase II reactions. These reactions are catalysed by transferase
Transferase
In biochemistry, a transferase is an enzyme that catalyzes the transfer of a functional group from one molecule to another . For example, an enzyme that catalyzed this reaction would be a transferase:In this example, A would be the donor, and B would be the acceptor...
enzymes such as glutathione S-transferase
Glutathione S-transferase
Enzymes of the glutathione S-transferase family are composed of many cytosolic, mitochondrial, and microsomal proteins. GSTs are present in eukaryotes and in prokaryotes, where they catalyze a variety of reactions and accept endogenous and xenobiotic substrates.GSTs can constitute up to 10% of...
s. Finally, in phase III, the conjugated xenobiotics may be further processed, before being recognised by efflux transporters
Efflux (microbiology)
Active efflux is a mechanism responsible for extrusion of toxic substances and antibiotics outside the cell; this is considered to be a vital part of xenobiotic metabolism...
and pumped out of cells.
The reactions in these pathways are of particular interest in medicine
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
as part of drug metabolism
Drug metabolism
Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
and as a factor contributing to multidrug resistance
Multidrug resistance
Multiple drug resistance or Multidrug resistance is a condition enabling a disease-causing organism to resist distinct drugs or chemicals of a wide variety of structure and function targeted at eradicating the organism...
in infectious disease
Infectious disease
Infectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...
s and cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
. The actions of some drugs as substrates or inhibitors
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of enzymes involved in xenobiotic metabolism are a common reason for hazardous drug interaction
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
s. These pathways are also important in environmental science
Environmental science
Environmental science is an interdisciplinary academic field that integrates physical and biological sciences, to the study of the environment, and the solution of environmental problems...
, with the xenobiotic metabolism of microorganism
Microorganism
A microorganism or microbe is a microscopic organism that comprises either a single cell , cell clusters, or no cell at all...
s determining whether a pollutant will be broken down during bioremediation
Bioremediation
Bioremediation is the use of microorganism metabolism to remove pollutants. Technologies can be generally classified as in situ or ex situ. In situ bioremediation involves treating the contaminated material at the site, while ex situ involves the removal of the contaminated material to be treated...
, or persist
Persistent organic pollutant
thumb|right|275px|State parties to the Stockholm Convention on Persistent Organic PollutantsPersistent organic pollutants are organic compounds that are resistant to environmental degradation through chemical, biological, and photolytic processes...
in the environment. The enzymes of xenobiotic metabolism, particularly the glutathione S-transferase
Glutathione S-transferase
Enzymes of the glutathione S-transferase family are composed of many cytosolic, mitochondrial, and microsomal proteins. GSTs are present in eukaryotes and in prokaryotes, where they catalyze a variety of reactions and accept endogenous and xenobiotic substrates.GSTs can constitute up to 10% of...
s are also important in agriculture, since they may produce resistance to pesticide
Pesticide
Pesticides are substances or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.A pesticide may be a chemical unicycle, biological agent , antimicrobial, disinfectant or device used against any pest...
s and herbicide
Herbicide
Herbicides, also commonly known as weedkillers, are pesticides used to kill unwanted plants. Selective herbicides kill specific targets while leaving the desired crop relatively unharmed. Some of these act by interfering with the growth of the weed and are often synthetic "imitations" of plant...
s.
Permeability barriers and detoxification
That the exact compounds an organism is exposed to will be largely unpredictable, and may differ widely over time, is a major characteristic of xenobiotic toxic stress. The major challenge faced by xenobiotic detoxification systems is that they must be able to remove the almost-limitless number of xenobiotic compounds from the complex mixture of chemicals involved in normal metabolismMetabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
. The solution that has evolved to address this problem is an elegant combination of physical barriers and low-specificity enzymatic
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
systems.
All organisms use cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
s as hydrophobic permeability barriers to control access to their internal environment. Polar compounds cannot diffuse across these cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
s, and the uptake of useful molecules is mediated through transport protein
Transport protein
A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, or macromolecules, such as another protein across a biological membrane. Transport proteins are integral membrane proteins; that is they exist within and span the membrane across which they...
s that specifically select substrates from the extracellular mixture. This selective uptake means that most hydrophilic
Hydrophile
A hydrophile, from the Greek "water" and φιλια "love," is a molecule or other molecular entity that is attracted to, and tends to be dissolved by water. A hydrophilic molecule or portion of a molecule is one that has a tendency to interact with or be dissolved by, water and other polar substances...
molecules cannot enter cells, since they are not recognised by any specific transporters. In contrast, the diffusion of hydrophobic
Hydrophobe
In chemistry, hydrophobicity is the physical property of a molecule that is repelled from a mass of water....
compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
-soluble xenobiotics using membrane barriers.
However, the existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics. These systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolise almost any non-polar compound. Useful metabolites are excluded since they are polar, and in general contain one or more charged groups.
The detoxification of the reactive by-products of normal metabolism cannot be achieved by the systems outlined above, because these species are derived from normal cellular constituents and usually share their polar characteristics. However, since these compounds are few in number, specific enzymes can recognize and remove them. Examples of these specific detoxification systems are the glyoxalase system
Glyoxalase system
The glyoxalase system is a set of enzymes that carry out the detoxification of methylglyoxal and the other reactive aldehydes that are produced as a normal part of metabolism...
, which removes the reactive aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
methylglyoxal, and the various antioxidant systems that eliminate reactive oxygen species.
Phases of detoxification
The metabolism of xenobiotics is often divided into three phases: modification, conjugation, and excretion. These reactions act in concert to detoxify xenobiotics and remove them from cells.Phase I - modification
In phase I, a variety of enzymes acts to introduce reactive and polar groups into their substrates. One of the most common modifications is hydroxylation catalysed by the cytochrome P-450-dependent mixed-function oxidase system. These enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, O- and S-dealkylation of substrates. The reaction mechanism of the P-450 oxidases proceeds through the reduction of cytochrome-bound oxygen and the generation of a highly-reactive oxyferryl species, according to the following scheme:Phase II - conjugation
In subsequent phase II reactions, these activated xenobiotic metabolites are conjugated with charged species such as glutathioneGlutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
(GSH), sulfate
Sulfate
In inorganic chemistry, a sulfate is a salt of sulfuric acid.-Chemical properties:...
, glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
, or glucuronic acid
Glucuronic acid
Glucuronic acid is a carboxylic acid. Its structure is similar to that of glucose. However, glucuronic acid's sixth carbon is oxidized to a carboxylic acid...
. These reactions are catalysed by a large group of broad-specificity transferases, which in combination can metabolise almost any hydrophobic compound that contains nucleophilic or electrophilic groups. One of the most important of these groups are the glutathione S-transferase
Glutathione S-transferase
Enzymes of the glutathione S-transferase family are composed of many cytosolic, mitochondrial, and microsomal proteins. GSTs are present in eukaryotes and in prokaryotes, where they catalyze a variety of reactions and accept endogenous and xenobiotic substrates.GSTs can constitute up to 10% of...
s (GSTs). The addition of large anionic groups (such as GSH) detoxifies reactive electrophile
Electrophile
In general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...
s and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported.
Phase III - further modification and excretion
After phase II reactions, the xenobiotic conjugates may be further metabolised. A common example is the processing of glutathione conjugates to acetylcysteine (mercapturic acid) conjugates. Here, the γ-glutamateGlutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
and glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
residues in the glutathione molecule are removed by Gamma-glutamyl transpeptidase and dipeptidase
Dipeptidase
Dipeptidases are enzymes secreted by enterocytes into the small intestine. Dipeptidases hydrolyze bound pairs of amino acids, called dipeptides....
s. In the final step, the cystine
Cystine
Cystine is a dimeric amino acid formed by the oxidation of two cysteine residues that covalently link to make a disulfide bond. This organosulfur compound has the formula 2. It is a white solid, and melts at 247-249 °C...
residue in the conjugate is acetylated.
Conjugates and their metabolites can be excreted from cells in phase III of their metabolism, with the anionic groups acting as affinity tags for a variety of membrane transporters of the multidrug resistance protein
P-glycoprotein
P-glycoprotein 1 also known as multidrug resistance protein 1 or ATP-binding cassette sub-family B member 1 or cluster of differentiation 243 is a glycoprotein that in humans is encoded by the ABCB1 gene...
(MRP) family. These proteins are members of the family of ATP-binding cassette transporters and can catalyse the ATP-dependent transport of a huge variety of hydrophobic anions, and thus act to remove phase II products to the extracellular medium, where they may be further metabolised or excreted.
Endogenous toxins
The detoxification of endogenous reactive metabolites such as peroxidePeroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...
s and reactive aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
s often cannot be achieved by the system described above. This is the result of these species' being derived from normal cellular constituents and usually sharing their polar characteristics. However, since these compounds are few in number, it is possible for enzymatic systems to utilize specific molecular recognition to recognize and remove them. The similarity of these molecules to useful metabolites therefore means that different detoxification enzymes are usually required for the metabolism of each group of endogenous toxins. Examples of these specific detoxification systems are the glyoxalase system
Glyoxalase system
The glyoxalase system is a set of enzymes that carry out the detoxification of methylglyoxal and the other reactive aldehydes that are produced as a normal part of metabolism...
, which acts to dispose of the reactive aldehyde methylglyoxal
Methylglyoxal
Methylglyoxal, also called pyruvaldehyde or 2-oxopropanal is the aldehyde form of pyruvic acid. It has two carbonyl groups, so it is a dicarbonyl compound. Methylglyoxal is both an aldehyde and a ketone....
, and the various antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
systems that remove reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
.
History
Studies on how people transform the substances that they ingest began in the mid-nineteenth century, with chemists discovering that organic chemicals such as benzaldehydeBenzaldehyde
Benzaldehyde is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. This colorless liquid has a characteristic pleasant almond-like odor...
could be oxidized and conjugated to amino acids in the human body. During the remainder of the nineteenth century, several other basic detoxification reactions were discovered, such as methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
, acetylation
Acetylation
Acetylation describes a reaction that introduces an acetyl functional group into a chemical compound...
, and sulfonation
Sulfonic acid
Sulfonic acid usually refers to a member of the class of organosulfur compounds with the general formula RS2–OH, where R is an alkyl or aryl. The formal part of acid, HS2–OH, are formally derivatives of the "parent" inorganic compound with the formula HSO2.-Preparation:Sulfonic acid is...
.
In the early twentieth century, work moved on to the investigation of the enzymes and pathways that were responsible for the production of these metabolites. This field became defined as a separate area of study with the publication by Richard Williams
Richard Tecwyn Williams
Richard Tecwyn Williams was a Welsh biochemist who founded the systematic study of xenobiotic metabolism with the publication of his book Detoxication mechanisms in 1947...
of the book Detoxication mechanisms in 1947. This modern biochemical research resulted in the identification of glutathione S-transferases in 1961, followed by the discovery of cytochrome P450s in 1962, and the realization of their central role in xenobiotic metabolism in 1963.
See also
- Drug designDrug designDrug design, also sometimes referred to as rational drug design or structure-based drug design, is the inventive process of finding new medications based on the knowledge of the biological target...
- Drug metabolismDrug metabolismDrug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems. This is a form of xenobiotic metabolism. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products...
- Microbial biodegradationMicrobial biodegradationInterest in the microbial biodegradation of pollutants has intensified in recent years as humanity strives to find sustainable ways to clean up contaminated environments...
- BiodegradationBiodegradationBiodegradation or biotic degradation or biotic decomposition is the chemical dissolution of materials by bacteria or other biological means...
- BioremediationBioremediationBioremediation is the use of microorganism metabolism to remove pollutants. Technologies can be generally classified as in situ or ex situ. In situ bioremediation involves treating the contaminated material at the site, while ex situ involves the removal of the contaminated material to be treated...
- AntioxidantAntioxidantAn antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
- SPORCalc, an example process for exploring xenobiotic and drug metabolism databases
External links
Databases- Drug metabolism database
- Directory of P450-containing Systems
- University of Minnesota Biocatalysis/Biodegradation Database
Drug metabolism
Microbial biodegradation
History