Where is cytochrome p450 produced

In hydrolysis you add water with the help of esterases, phosphatases and others. Here are some slides if you are interested in learning more.

Phase I transformation of toxins involves a large group of isoenzymes. Although there are several types of phase I enzymes, the most common enzymes are collectively called the cytochrome P CYP system. The P stands for pigment and the nm is the wavelength of light absorption. CYP contains an iron protoporphyrin prosthetic group heme. CYP catalyzes primarily oxidation, reduction, and hydrolysis, reactions which generally expose a functional group or adds a functional group.

This is followed by the Phase II processes of methylation , glucuronidation , glutathione conjugation , amino acid conjugation, sulfation , or acetylation , which adds a compound to the functional group that was exposed or added in Phase I. Ultimately the process is changing a lipophilic, or fat loving compound into a more polar or water loving compound, which is now in a form easier for the body to remove.

It should also be mentioned that the CYP system is not just removing toxins, it is also producing some compounds such as cholesterol, steroids, fatty acids and vitamin D. In humans more than 50 enzymes make up the cytochrome P system. It is thought humans developed so many isoenzymes to keep up with the new alkaloids made by plants. The idea is that humans and other animals developed new isoenzymes to metabolize new plant alkaloids, the plants then developed new alkaloids and the animals respond again etc.

It is known that the gene for CYP has existed for more then 3. Each enzyme works best in detoxifying certain types of chemicals, but with considerable overlap in activity among the enzymes, the system allows for some degree of back up assistance if an enzyme is not available. Each enzyme is encoded by separate genes. Most CYP genes are subject to genetic polymorphism which means we all have different abilities to transform toxins.

The CYP enzymes are categorized into families and subfamilies. They are classified into different families according to the amino acid similarities of the encoding proteins. CYP genes in families 1—3 encode for 22 different isoforms, mainly involved in the metabolism of drugs and other xenobiotics, whereas families 4—51 are generally involved in the biosynthesis and metabolism of endogenous compounds. The CYP are heme based enzymes located in the smooth endoplasmic reticulum, largely concentrated in liver cells, and mucosal intestinal cells, but also found in a variety of other bodily systems to a lesser degree.

The brain has additionally been identified as having a lot of P enzyme activity. The primary role for the P system seems to be one of metabolism, and detoxification of compounds after they have been consumed as part of food products. This accounts for the high concentrations of these enzymes located in the liver and small intestine. CYP enzymes metabolize toxins slow compared to other enzymes.

The slower speed, is made up for by devoting more space and increased production facilities for cyp enzymes. Those people who have decreased CYP system activity will have slowed caffeine metabolism, and be more effected by caffeine, while those with an overactive system will be relatively unaffected by caffeine drinks. Caffeine is an example of a chemical directly neutralized by phase I. One way of objectively determining the activity of phase I is to measure how efficiently a person detoxifies caffeine.

Using this test, a surprising fivefold difference in the detoxification rates of apparently healthy adults has been discovered. When cytochrome P metabolizes a toxin, it chemically transforms it to a less toxic, and excretable form, or converts it to an intermediate form that undergoes further biotransformation through Phase II.

That intermediate form may be less toxic or it sometimes becomes a more chemically active more toxic form and this is called a bioactivation reaction.

Making a toxin water-soluble allows its excretion by the kidneys. Transforming a toxin to a more chemically reactive form means it needs to be metabolized by the phase II enzymes, or it becomes more hazardous in the body than the original substance prior to Phase I biotransformation. When the metabolites of Phase I are made in excess of what Phase II can conjugate, there is a back up of toxic metabolites and this can be a problem.

Phase II must be competent, and able to handle Phase I metabolites to protect the body against diseases such as cancer. A significant side-effect of phase I transformation detoxification is the production of free radicals. For each molecule of unwanted substance toxin metabolized by phase I, one molecule of free radical is generated. Without adequate free radical defenses, every time the liver neutralizes a toxin, it is damaged by the free radicals produced.

This is where antioxidants come in. Antioxidants needed for protection from these free radicals that are produced. Many antioxidants can be involved in this process.

They include vitamin C ascorbic acid , carotenes vitamin A , tocopherols vitamin E , copper, manganese, selenium, zinc, coenzyme q10, bioflavonoids, silymarin, thiols found in alliums such as garlic, and onions, as well as cruciferous vegetables such as brussell sprouts and cabbage.

By far the most important antioxidant in phase I and phase II biotransformation is glutathione. The most important antioxidant for neutralizing the free radicals produced in phase I is glutathione.

In the process of neutralizing free radicals, however, the reduced form of glutathione GSH , is oxidized to glutathione disulfide GSSG.

The reduced glutathione is required for one of the key phase II detoxification processes glutathione conjugation besides it's activity as an antioxidant. When high levels of toxin exposure produce so many free radicals from phase I detoxification that the glutathione is depleted, the phase II processes dependent upon glutathione stop.

Check out the article on glutathione for details on this and other methods to increase glutalthione production. The toxins transformed into activated intermediates by phase I are substantially more reactive. Unless quickly removed from the body by phase II transformation detoxification mechanisms, they can cause widespread problems, such as induction of cancer.

Therefore, the rate at which phase I produces activated intermediates must be balanced by the rate at which phase II finishes their processing. People with a very active phase I detoxification system coupled with slow, or inactive phase II enzymes are termed pathological detoxifiers. These people suffer unusually severe toxic reactions to environmental poisons. An imbalance between phase I and phase II can also occur when a person is exposed to large amounts of toxins, or exposed to toxins for a long period of time.

In these situations, the critical nutrients needed for phase II transformation detoxification are depleted, which allows the highly toxic activated intermediates to build up. As with all enzymes, the cytochrome CYP requires several nutrients to function, such as copper, magnesium, zinc and vitamin C. A considerable amount of research has found that various substances activate CYP enzymes while others inhibit it.

Obviously, as long as Phase II is working, it is beneficial to improve phase I transformation in order to eliminate toxins as soon as possible. This is best accomplished by providing the needed nutrients and non-toxic stimulants while avoiding those substances that are toxic. Additionally, you have to be aware that increasing, or decreasing Phase I will alter how many drugs are metabolized, and may cause trouble for people who are on medications.

Several CYP enzymes have been identified as more important than others in oxidative metabolism. Their job is to oxidize exogenous and endogenous chemicals to be able to excrete them from the body.

To better understand this system it helps to know a few important words. The substances that the biotransformation system works on are called substrates. The substances that increase any part of the biotransformational system are called inducers. The substances that decrease part of the biotransformational system are called inhibitors.

A substrate is a material or substance that an enzyme acts upon. The substrate may be a toxin or hormone, or other exogenous, or endogenous substance that is acted upon and undergoes biotransformation.

A substrate is not necessarily a toxin but often can be. A substrate can also be a necessary substance for bodily functions. Something that activates enzymes, makes the enzyme work better, allows the enzyme to work or otherwise stimulates the process of biotransformation.

Substrates usually induce the creation of enzymes needed to break them down. For this reason substrates are often included in the list of inducers. Something that deactivates enzymes, decreases the enzyme from working well, or otherwise decreases biotransformation.

Sometimes a substrate can cause competitive inhibition. In this case the substance is both a substrate and an inhibitor. Keep in mind that our knowledge of this system is often from studies completed outside of the body in vitro , or on constituents from food or herbs rather than the food, or herb itself.

Neither of these scenarios are real life situations, and therefore the research may give us hints at reality, or completely miss the mark. This is especially true when only a constituent of a food or herb is studied.

We can't assume the whole food or whole herb will have the same effect, although they may. One food or herb can have both inducers and inhibitors in the item. Still it is good to know about this data.

Some foods such as grapefruit have definitely been shown clinically to be inhibitors of CYP A considerable amount of research has found various substances activate, or inhibit cytochrome P enzymes.

This research has become very useful to practitioners. Obviously, it is beneficial to improve phase I transformation in order to eliminate toxins as soon as possible.

This is best accomplished by providing the needed nutrients that support and enhance the system, including non-toxic stimulants, while avoiding those substances that are inducers, but toxic.

Enzyme induction occurs for CYP with vitamins and minerals that are needed for the system to operate. The activity of CYP oxidases vary across the population due to polymorphism from one person to another. This is seen clinically in the different reactions people have to drugs, or especially when multiple drugs are co-administered.

Most of the serious drug interactions are due to the interference of the metabolic clearance of one drug by another drug. Interactions between grapefruit juice and cardiovascular drugs. American journal of cardiovascular drugs : drugs, devices, and other interventions.

Grapefruit juice-drug interactions. British journal of clinical pharmacology. Pharmacogenomics of tamoxifen therapy. Clinical chemistry. Clinical pharmacology and therapeutics. Science New York, N. The Journal of pharmacology and experimental therapeutics. Effect of concomitant CYP2D6 inhibitor use and tamoxifen adherence on breast cancer recurrence in early-stage breast cancer.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Estabrook Ronald W. A passion for Ps rememberances of the early history of research on cytochrome P Drug metabolism and disposition: the biological fate of chemicals.

Biochemische Zeitschrift. Gibson G. Introduction to Drug Metabolism 3rd ed. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Indiana School of Medicine P drug interaction chart. Indiana University. Antimicrobial agents and chemotherapy. Johansson Inger, Ingelman-Sundberg Magnus. Genetic polymorphism and toxicology--with emphasis on cytochrome p Toxicological sciences : an official journal of the Society of Toxicology.

Kato Motohiro. Intestinal first-pass metabolism of CYP3A4 substrates. Drug metabolism and pharmacokinetics. Kelly C. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: A population based cohort study. British Medical Journal.

Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. The pharmacogenomics journal. Pigments of rat liver microsomes.

Archives of biochemistry and biophysics. Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. National Comprehensive Cancer Network. NCCN Guidelines. Breast Cancer, Version 1. Nelson D. The cytochrome P homepage.

Human Genomics. Gleevec imatinib mesylate package insert. Novartis Pharmaceuticals. Torisel temsirolimus package insert. Vfend voriconazole package insert. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group trial. Journal of the National Cancer Institute.

Fluoxetine-related death in a child with cytochrome P 2D6 genetic deficiency. Journal of child and adolescent psychopharmacology. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication. Anesthesia and analgesia. The Medical Letter of Drugs and Therapeutics.

New simvastatin dosing recommendations. For example, St. On the other hand, grapefruit juice is a known inhibitor of CYP3A4 and can have opposite effects. Nicotine is another compound that induces CYP1A2, and both nicotine and caffeine serve as substrates to CYP1A2, explaining a potential mechanism behind the phenomenon of increased tolerance to caffeine among smokers.

Within cells, CYP enzymes closely associate with the endoplasmic reticulum and inner mitochondrial membrane activity. The enzymes surrounding the endoplasmic reticulum further express their action to metabolize external substances such as drugs, whereas the mitochondrial enzymes focus on internal substances such as steroid hormone metabolism and fatty acid regulation.

Activation of these enzymes is prompted by transcription, as evidenced by varying degrees of expression in correspondence to mRNA levels. The purpose of drug metabolism is to safely administer the active constituent s accordingly and transform an exogenous compound into a more hydrophilic substance. Once it is water-soluble, drugs and their metabolic byproducts travel to the kidneys, where they are then filtered and excreted from the body.

Reactions that occur during this phase include oxidation, reduction, and hydrolysis - oxidation being the chief mode of metabolism. CYP alleles group as wild-type vs. Persons who inherit two wild-type alleles will generally be extensive metabolizers normal , whereas persons with two variant alleles will be poor metabolizers defective. Those that carry one allele of each are intermediate metabolizers. There is another group known as ultrarapid metabolizers who inherit more than two wild-type alleles, which are subject to their own potential drug effects.

Genetic polymorphisms are one theory regarding why certain people exhibit varying tolerance levels of a specific drug. A poor metabolizer may express signs of toxicity at drug dosages that an extensive metabolizer could tolerate. Interestingly, females expressed a higher concentration of CYP enzymes, indicating one reason females are subject to metabolize drugs faster.

Research in the molecular field of CYP enzymes is still developing, and the addition of the human genome project will only prove more vital as an element in personalized medicine. Still, it is a known fact that polymorphism plays a significant role in drug metabolism due to the inherited CYP activity of individuals. CYP enzymes undergo a multitude of reactions, each with slightly different variations depending on the enzyme and substrate involved.

As monooxygenases, CYP's primary role is the addition of an oxygen atom to the substrate. In general, the mechanism CYP exhibits in catalyzing reactions depends on a few simple steps. Drugs and other compounds that already have a free polar group can skip phase I, where they will proceed directly to phase II for conjugation. As mentioned before, inflammatory states can play a determinant factor in CYP expression. Diseases of the liver, such as cirrhosis, can lead to fibrotic scarring causing damage to hepatocytes and decreased metabolic capacity.

The clinical effects of cirrhosis can be further related to CYP enzymes. Due to its role in steroidogenesis and metabolism, some of the hormonal effects seen in cirrhotics, such as gynecomastia and spider angiomas, can be related to an aberrant change in CYP activity. Due to the presence of CYP enzymes in intestinal wall tissue, diseases of the small and large bowels can affect CYP enzymes as well. While the brush-border enzymes and other parts of the intestines play a limited role in the metabolism of drugs and other xenobiotics, their role in drug absorption is their most significant contributing feature.

This activity can play a factor in altering the oral bioavailability of drugs, rendering some treatments ineffective or greater than expected, and creating greater responsibility on the clinician's part to dose the medication to provide therapeutic benefit appropriately. Grapefruit juice is an example of a natural compound that affects drug metabolism at the site of the intestinal wall in small amounts. Absorbed by the small intestine, a natural flavonoid found in grapefruits known as naringin acts locally to inhibit CYP3A4 enterocytes, potentially lead to greater plasma concentrations of 3A4-mediated drugs.

Infections, both widespread systemic issues and organ-specific conditions, have been shown to decrease CYP expression as well, through cytokine-mediated downregulation. All individuals on drug therapy should receive an evaluation to check for any concurrent medications that may influence the activity of another drug based on their effects on CYP activity.

Based on the characteristics of the drug's profile, CYP enzymes can be either induced or inhibited-marking a significant area of concern in patients due to issues with metabolism and clearance. This can cause considerable adverse effects for patients as medications may either accumulate to toxic levels or clear from the system too rapidly, leading to treatment failure.

Also, clinicians must be aware of naturally occurring compounds that can alter the actions of CYP enzymes, such as grapefruit juice, nicotine-containing products, and St. Special precautions are necessary for patients who have decreased baseline activity or injury to CYP enzymes.

Looking into the future of medical advancements regarding pharmacogenomics, genetic polymorphisms of CYP alleles could take precedent in determining the proper therapy and drug dose for individual patients. With this information, we would better be able to predict drug response in patients. Common cytochrome p inducers, inhibitors, and substrates of the primary isozymes mentioned in this article are listed below. It is crucial to keep in mind that many drugs that serve as either an inducer or inhibitor of an isozyme also act as a substrate.

For the sake of eliminating redundancy, they were not mentioned twice here. This book is distributed under the terms of the Creative Commons Attribution 4. Turn recording back on. National Center for Biotechnology Information , U. StatPearls [Internet]. Search term. Introduction Response to drugs varies considerably from person to person, and their clinical outcomes, ranging from treatment failure to adverse drug reactions, can be largely attributed to drug metabolism.

Fundamentals Cytochrome p is a superfamily of membrane-bound hemoprotein isozymes with distinct classifications. Issues of Concern Due to their role in detoxifying potentially toxigenic xenobiotics and widespread nature throughout numerous organ systems, CYP enzymes are subject to a myriad of potential reactions and serve as a backbone in clinical research.