Crystal structure of cyp24a1, a mitochondrial cytochrome p450 involved in vitamin d metabolism andrew j. Cytochrome p450 p450, cyp research provides many opportunities for the application of kinetic isotope effect kie strategies. Feb 26, 2019 the cytochrome p450 cyp enzymes are a protein superfamily involved in the synthesis and metabolism of drugs, toxins and normal cellular components. The strength of enzyme inhibition or stimulation is indicated by the width of the lines and the number of terminal plus or minus signs. Cytochrome p450 enzymes in the metabolism of vitamin d. Cytochrome p450 p450 enzymes include a family of related enzymes that are involved in metabolism of vitamins, steroids, fatty acids, and other chemicals. Enzymes of the cytochrome p450 cyp superfamily are all hemecontaining enzymes. We now report a novel cyp3a4dependent pathway, the 4hydroxylation of 25. Dec 24, 2019 toggle navigation cytochrome p450 mediated drug metabolism and toxicity supplementary materialsnutrients1100374s001.
Pdf metabolism of vitamin d3 by cytochromes p450 researchgate. Riboflavin was found to be the most effective inhibitor of diclofenac hydroxylation by cytochrome p450 3a4, as was demonstrated by comparing the influence of vitamin b group b1, b2, and b6 at the same. Cytochrome p450 bm3 cyp102a1 from the soil bacterium. Hector deluca had demonstrated that p450catalyzed hydroxylation of vitamin d 3 was important in generating the most active forms 49, 50, and subsequent work has shown the importance of several p450s in the activation and catabolism of vitamin d 55 57. Johns wort also significantly decreases verapamil bioavailability through induction of firstpass metabolism in the gut. It is the substrate for a second hydroxylase, the mitochondrial cytochrome p450 27b1, which is found abundantly in the kidney, resulting in the production of the most biologically active form of vitamin d 3, 1. An important reference on different alleles is the human cytochrome p450 cyp allele nomenclature committees web page. The number of known p450 enzymes exceeds, while the endogenous substrates of most of them remain unknown. In recent years, various in vitro assays have been developed and used routinely to assess the potential for drugdrug interactions due to. Metabolic deactivation of 1,25oh2d3 is initiated by modification of the vitamin d side chain, as carried out by the mitochondrial cytochrome p450 24a1 cyp24a1. These genes code for enzymes that can have a role in. P450s collectively catalyze oxidations of more substrates than any other group of enzymes, and ch bond cleavage is a major feature in a large fraction of these reactions. Nov 17, 2006 three independent cytochrome p450 enzyme families catalyze the three ratelimiting hydroxylation steps in the phenylpropanoid pathway leading to the biosynthesis of lignin and numerous other phenolic compounds in plants.
Cytochrome p450 3a4 cyp3a4 is a multifunctional enzyme involved in both xenobiotic and endobiotic metabolism. Cyp3a4 is a human microsomal vitamin d 25a american society. Pdf the vitamin d3 25hydroxylase cyp27a1, 25hydroxyvitamin d3 1alpha hydroxylase cyp27b1 and 1alpha,25dihydroxyvitamin d3. Expression of cyp24a1 is upregulated to attenuate vitamin d signaling associated with calcium homeostasis and cellular growth processes. Comparison of cytochrome p450 cyp genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternativesplice variants. Crystal structure of cyp24a1, a mitochondrial cytochrome. During the last 1015 years, cytochrome p450 cyp 2c8 has emerged as an important drugmetabolizing enzyme. Cytochromes p450 in phenolic metabolism springerlink. Cytochrome p450 family 3 subfamily a cyp3a enzymes comprise. In some individuals, mineral homeostasis can be disrupted by longterm therapy with certain antiepileptic drugs and the antimicrobial agent rifampin, resulting in druginduced osteomalacia, which is attributed to vitamin d deficiency. Cytochrome p450 inducer an overview sciencedirect topics. These enzymes are located either in the endoplasmic reticulum er e. Cyp24a1 itself has less than 40% sequence identity with other p450s.
The activation of vitamin d3 is accomplished by sequential steps of 25 hydroxylation to produce the main circulating form, 25hydroxyvitamin d. Cytochrome p450 enzymes also function to metabolize potentially toxic compounds, including drugs and. As many as 90% of cancers are suspected to be due to environmental carcinogens. Cytochrome p450 research and the journal of biological chemistry. Enzymes of the cytochrome p450 p450 or cyp super family are the most versatile and important class of drugmetabolizing enzymes that are induced in mammalian skin in response to xenobiotic exposure. Introduction cytochrome p450 cyp450 is the generic name given to a large family of versatile enzymes that metabolise most drugs and a myriad of chemicals of toxicological importance termed xenobiotic metabolism. Regulation of vitamin d metabolizing enzymes in murine. An inducible cytochrome p450 3a4dependent vitamin d catabolic. Specificity of the redox complex between cytochrome p450 24a1. Deficiency in p450 27b1 is a cause of rickets disease 58, 59. Cytochrome p450 cyp is the most important phase i drugmetabolizing enzyme system, responsible for the metabolism of a variety of xenobiotics including therapeutic drugs and some important endogenous substances such as steroids burchell et al.
Mitochondrial p450 enzymes catalyze highly specific reactions in the biosynthesis and degradation of hormones. As with all mitochondrial cyps, the functional enzyme activity for mitochondrial vitamin drelated cyps e. Aoyama k, yoshinari k, kim hj, nagata k, yamazoe y. Comprehensive summ aries of upps ala disserta tions from the fa culty of pharmacy 266. Degtyarenko and peter fabian contains a wealth of information and links. Cyp24 vitamin d degradation 1 subfamily, 1 gene cyp24a1. According to goljan, precursors of 25ohd have increased metabolism with induction of cytochrome p450. Schematic diagram of vitamin d metabolism and cytochrom openi. The most intensively studied route of drug metabolism is the p450 catalysed mixedfunction. The term cytochrome p450 stems from the fact that the proteins are members of the cytochrome heme containing family of proteins and that when the heme moiety is complexed with carbon monoxide the maximum absorption of light occurs at a wavelength of 450 nm.
Cyp2c8 is highly expressed in human liver and is known to metabolize more than 100 drugs. Cytochrome p450 p450 induction is one of the factors that can affect the pharmacokinetics of a drug molecule upon multiple dosing, and it can result in pharmacokinetic drugdrug interactions with coadministered drugs causing potential therapeutic failures. Electroanalysis of cytochrome p450 3a4 catalytic properties. Cytochrome p450 enzymes also function to metabolize potentially toxic compounds, including drugs and products of endogenous metabolism such as bilirubin, principally in the liver. The enzymes responsible for metabolizing vitamin d springerlink. In addition to its role in vitamin d metabolism, cyp24a1 is involved in catabolism of vitamin d analogs, thereby reducing their efficacy. The crystal structure of cyp24a1, a mitochondrial cytochrome. Feb 19, 2010 cytochrome p450 cyp 24a1 catalyzes the sidechain oxidation of the hormonal form of vitamin d. An inducible cytochrome p450 3a4dependent vitamin d. Simultaneous expression of plural forms of human cytochrome p450 at desired ratios in hepg2 cells. Cytochrome p450 enzymes in th e metabolism of vitamin d 3. Vitamin d3 is critical for the regulation of calcium and phosphate homeostasis.
Cytochrome p450 enzymes are present in most tissues of the body, and play important roles in hormone synthesis and breakdown including estrogen and testosterone synthesis and metabolism, cholesterol synthesis, and vitamin d metabolism. Role of cytochrome p450 2c8 in drug metabolism and interactions. Cytochrome p450mediated metabolism of vitamin d april 20. Comparison of cytochrome p450 cyp genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and. Cytochrome p450 enzymes in the bioactivation of vitamin d. We investigated the association between genetic polymorphisms in cytochrome p450 cyp2r1, cyp24a1, and the cyp3a family with nonsummer plasma concentrations of vitamin d metabolites 25hydroxyvitamin d 3 25oh d 3 and proportion 24,25dihydroxyvitamin d 3 24,25oh 2 d 3 among healthy individuals of subsaharan african and european ancestry, matched on age within 5 years. Cytochrome p450 enzymes in drug metabolism and chemical. Crystal structure of cyp24a1, a mitochondrial cytochrome p450. The role of cytochrome p450 enzymes in endogenous signalling. Cytochromes p450 henceforth p450s are involved in a variety of metabolic and biosynthetic processes. Cyp3a4 is a vitamin d24 and 25hydroxylase oxford academic. Enterohepatic circulation of vitamin d metabolites and their conjugates will be also discussed.
Excesses of xenobiotic toxicity can cause an overutilization of the cytochrome p450 enzymes, and can result in dangerous free radicals. Cytochrome p450 oxidoreductase deficiency wikipedia. Cyp24a1 function relies on electron transfer from the soluble ferredoxin protein adrenodoxin. Cyp2c8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the number is. D 2 is produced by uvb irradiation of the ergosterol in plants and fungi e. Their characterization at the molecular and enzymatic level has revealed an unexpected complexity of phenolic metabolism as the major route involves shikimatequinate esters.
The cytochrome p450 p450 or cyp isoenzymes are a group of hemecontaining enzymes embedded primarily in the lipid bilayer of the endoplasmic reticulum of hepatocytes, it takes part in the metabolism of many drugs, steroids and carcinogens 1. Cytochrome p450 enzymes also play a number of essential roles in the synthesis of normal cellular compounds. Cyp3a4, the most abundant cytochrome p450 enzyme in human liver and intestine, had. All p450 enzymes exhibit similarity in their structure and general mechanism of action. Cyp3a4, cyp2b6, and cyp2c9 is regulated by the vitamin d receptor pathway in primary human hepatocytes. Schematic diagram of vitamin d metabolism and cytochrome p450 mediated drug effects. Cytochrome p450 enzyme inhibition is indicated by broken lines and stimulation by solid lines. Cytochrome p450mediated metabolism of vitamin d ncbi. The vitamin d in fish is d 3, whereas that used for fortification is often d 2 ergocalciferol. Thus, cyp3a4 is a hepatic microsomal vitamin d 25hydroxylase.
P450s also play an important role in microorganisms in the use of various organic compounds as carbon sources and in the production of important natural products such as antibiotics. At the same time, cyp have numerous important roles in endogenous and exogenous substrate metabolism in the skin. Most foods with the exception of fatty fish contain little vitamin d unless fortified. Vitamin d metabolism, mechanism of action, and clinical. Clinical importance of the cytochromes p450 the lancet.
Cyp3a7 enzymes have no established role in vitamin d metabolism, yet. Vitamin d is a generic name for the antirachitic agents capable of curing rickets of which vitamin d3 is the major constituent. Ancestryadjusted vitamin d metabolite concentrations in. Cytochromes p450 and metabolism of xenobiotics springerlink.
Sixteen hepatic recombinant microsomal cytochrome p450 enzymes ex. The metabolism of 25ohd3 was fully characterized in vitro. P450s collectively catalyze oxidations of more substrates than any other group of enzymes, and c h bond cleavage is a major feature in a large fraction of these reactions. The human cytochrome p450 cyp superfamily comprises 57 genes. Interplay between vitamin d and the drug metabolizing. In addition, many drugs inhibit the cytochrome p450 enzymes and can cause further damage to the liver. The vitamin d signal transduction system involves a series of cytochrome p450containing sterol hydroxylases to generate and degrade the active hormone, 1. Cytochrome p450mediated drug metabolism and toxicity. For instance, special cytochrome p450 enzymes are built to perform chemical steps in the construction of steroids, vitamins a and d, and lipidlike eicosanoid molecules involved in signaling. The three main steps in vitamin d metabolism, 25hydroxylation, 1.
For example, they participate in the metabolism of therapeutic drugs, fatty acids. The cytochrome p450 cyp enzymes are a protein superfamily involved in the synthesis and metabolism of drugs, toxins and normal cellular components. Cyp3a4 was the predominant source of 25ohd3 hydroxylation by human liver microsomes, with the. This article about a disease, disorder, or medical condition is a stub. Effect of health foods on cytochrome p450mediated drug. Isolation and characterization of a cytochrome p450 from rat liver kidney. Cytochrome p450 cyp enzymes the medical biochemistry page.
Nov 11, 2003 in addition, p450s participate in the metabolism of sex hormones, vitamin d, and bile acids in mammals 1, 2. An excellent cytochrome p450 webpage is david nelsons. The liver contains most of the p450 enzymes in the body but other types of tissues such as kidney, lung, intestine, adrenal, brain and olfactory portion of the nose, contain cytochrome p450 enzymes 30, 3841. Role of cytochrome p450 in drug interactions nutrition. A cytochrome p450 enzyme in pig kidney that catalyzes the hydroxylations of vitamin d 3 and c 27sterols was.
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