Cytochrome P450 (CYP) Enzymes



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Introduction to Cytochrome P450 (CYP) Enzymes

 

 

 

 

 

 

 

 

 

 

 

Enzymes of the cytochrome P450 (CYP) superfamily are all heme-containing enzymes that are 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. The CYP enzymes are involved in numerous biosynthetic and metabolic pathways. The most significant functions of the CYP family enzymes are the synthesis and metabolism of lipids such as fatty acids and sterols and in the metabolism of xenobiotic compounds such as therapeutic drugs and foreign chemicals. With respect to lipid metabolism members of the large CYP family metabolize the clinically relevant polyunsaturated fatty acids (PUFAs) of the omega-3 and omega-6 families. These PUFAs include arachidonic acid (omega-6) and the omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The CYP enzymes are also critical in the synthesis and metabolism of cholesterol and bile acids as well as vitamin A (specifically retionic acid) and vitamin D.

Within the human genome there are 57 CYP genes with several being non-coding pseudogenes. These 57 genes are divided into 18 subfamilies where several subfamilies have multiple members that includes both active and pseudogenes. For example the CYP2 subfamily of genes includes 36 members with 16 of the genes expressing funcitonal enzymes. The bulk of the CYP enzymes in humans can be divided into two broad groups based upon their predominant site of biological function. These two groups include the microsomal CYPs and the mitochondrial CYPs. The microsomal CYPs transfer electorns from NADPH to the cytochrome P450 via the associated cytochrome P450 oxidoreductase activity. Cytochrome P450 oxidoreductase is encoded by the POR gene. Mutations in the POR gene are associated with a form of congenital adrenal hyperplasia (CAH) characterized by ambiguous genitalia in both males and females and skeletal malformations. The mitochondrial CYP enzymes utilize ferredoxin 1 (encoded by the FDX1 gene: protein also called adrenodoxin) and ferredoxin reductase (encoded by the FDXR gene; protein also called adrenodoxin reductase) in the transfer of electrons from NADPH to the cytochrome P450. Other CYP enzymes do not utilize an external (associated) reducing agent or protein such as is the case for thromboxane A synthase 1, TBXAS1 (classified in the CYP nomenclature as CYP5A1) and prostacyclin I2 synthase, PTGIS (classified in the CYP nomenclature as CYP8A1).

Another related family of P450 cytochromes are the cytochrome b5 proteins. Humans express two cytochrome b5 genes identified as CYB5A and CYB5B. Associated with cytochrome b5 activity is a member of the cytochrome b5 reductase family. Humans express four cytochrome b5 reductase genes identified as CYB5R1, CYB5R2, CYB5R3, and CYB5R4. The cytochrome b5 reductase activity is commonly referred to as methemoglobin reductase due to its initial characterization as the activity responsible for the reduction of ferric iron (Fe3+) in methemoglobin back to the normal ferrous (Fe2+) state.

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Human CYP Enzyme Family Members

CYP Family Family Members Activities / Comments
1 two subfamilies: A and B

CYP1A1, CYP1A2, CYP1B1
CYP1 family member genes transcriptionally activated by the aryl hydrocarbon receptor (AhR) and the aryl hydrocarbon receptor nuclear translocator (ARNT) heterodimeric transcription factor

CYP1A1 is a major extra-hepatic (non-liver) cytochrome P450 enzyme; involved in metabolism of numerous endogenous hormones, drugs, and xenobiotic compounds into carcinogenic derviatives such as the arylamines and polycyclic aromatic hydrocarbons (PAH); numerous polymorphisms in gene correlated to development of various cancers
CYP1A2 possesses monoxygenase and epoxygenase activities; metabolizes polyunsaturated fatty acids (PUFA) into potent signaling molecules; metabolizes xenobiotics such as polycyclic aromatic hydrocarbons (PAH) into carcinogenic compounds; metabolizes caffeine, acetaminophen, numerous antidepressants and antipsychotics, and many other commonly prescribed drugs
CYP1B1 metabolizes polycyclic aromatic hydrocarbons (PAH) into carcinogenic compounds
2 eleven subfamilies: A, B, C, D, E, F, J, R, S, U, W

CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1
total number of genes in the CYP2 family is 36 with 16 expressing active enzymes and the rest encoding pseudogenes

CYP2A6 principally involved in the metabolism of nicotine, also metabolizes numerous drugs including the blood thinner coumarin; metabolizes several carcinogenic compounds such as N-nitrosodiethylamine (NDEA); only enzyme that can 7-hydroxylate coumarin and therefore the measurment of 7-hydroxycoumarin is a diagnostic for the level of CYP2A6 activity
CYP2B6 metabolizes nicotine, the anti-cancer drugs cyclophosphamide and ifosfamide, and several other xenobiotic compounds
CYP2C8 functions as an expoxygenase to convert long-chain polyunsaturated fatty acids (PUFA) such as linoleic acid, arachidonic acid, and the physiologically significant omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to their biologically active epoxide forms
CYP2C9 represents a major drug (over 100 therapeutic molecules) and xenobiotic metabolizing enzyme in the liver; constitutes nearly 20% of the total hepatic cytochrome P450 activity in this organ; possesses epoxygenase activity and will convert several PUFA into bioactive lipids; numerous activity variants classified and discussed below
CYP2C19 metabolizes numerous therapeutic drugs such as the antiplatelet drug clopidogrel, antidepressants, antiepileptics, the proton pump inhibitors (e.g. omeprazole) used to treat acid reflux, and the anti-anxiety benzodiazepines; numerous activity variants classified and discussed below
CYP2D6: major drug metabolizing enzyme responsible for the metabolism of 20%-25% of commonly prescribed drugs including beta blockers, antidepressants, opioids, anti-cancer, and antipsychotics; over 160 characterized polymorphisms in the gene resulting in differences in catalytic activity; numerous activity variants classified and discussed below
CYP2E1 is the enzyme responsible for ethanol metabolism via the microsomal ethanol oxidizing system, MEOS; expression of the hepatic CYP2E1 gene induced in chronic alcohol consumption leading to enhanced heptotoxicity of ethanol; also involved in the metabolism of numerous other small polar molecules; certain protoxic carcinogens are converted to active forms via CYP2E1
CYP2J2 is a major enzyme responsible for the conversion of polyunsaturated fatty acids (PUFA) into bioactive signaling lipids; principal substrates are linoleic acid, arachidonic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)
CYP2R1 is commonly known as vitamin D 25-hydroxylase or just 25-hydroxylase; converts vitamin D3 to 25-hydroxyvitamin D3 in the liver which is then released to the blood
CYP2U1 functions as a hydroxylase that ω-hydroxylates poly unsaturated fatty acids (PUFA) such as arachidonic acid and docosahexaenoic acid (DHA)
3 CYP3A4, CYP3A5, CYP3A7, CYP3A43 CYP3A4 is a glucocorticoid-inducible enzyme; involved in the metabolism of cholesterol to 4β-hydroxycholesterol; major drug and other xenobiotic metabolizing enzyme
CYP3A5, together with CYP3A4, is responsible for 50% of drug metabolism mediated by cytochrome P450 enzymes; numerous alleles of the gene result is variable enzyme activities
CYP3A7 hydroxylates testosterone and dehydroepiandrosterone 3-sulfate (DHEA-S)
CYP3A43 exhibits a low level of testosterone 6β-hydroxylase activity
4 six subfamilies: A, B, F, V, X, Z

CYP4A11, CYP4A22, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4F22, CYP4V2, CYP4X1, CYP4Z1
total number of genes in the CYP2 family is 38 with 12 expressing active enzymes and the rest encoding pseudogenes

CYP4A11 ω-hydroxylates lauric, myristic, palmitic, oleic, and arachidonic acids
CYP4B1 ω-hydroxylates medium-chainfatty acids; important xenobiotic metabolizing enzyme for protoxic molecules (their metabolism makes them toxic) such as valproic acid, 3-methylindole, 4-ipomeanol, 3-methoxy-4-aminoazobenzene, as well as many other aromatic amines
CYP4F2 ω-hydroxylates α-tocopherols (vitamin E) and arachidonic acid
CYP4F3 generates two proteins (CYP4F3A and CYP4F3B) via alternative promoter useage and alternative mRNA splicing; CYP4F3A involved in ω-hydroxylation and degradation of leukotriene B4 (LTB4), CYP4F3B exhibits higher affinity for arachidonic acid
CYP4F8 ω-hydroxylates prostaglandin H2 (PGH2)
CYP4F11 primary substrates are long-chain 3-hydroxydicarboxylic acids (3-OHDCAs)
CYP4F12 involved in ω-hydroxylation and degradation of leukotriene B4 (LTB4) and certain antihistaminic drugs such as the histamine H1 receptor antagonist ebastine
CYP4F22 ω-hydroxylates very long-chain fatty acids (VLCFA) present in ω-oxyacyl-sphingosine complexes; reaction represents a critical step in the delivery of VLCFA to the stratum corneum near the skin surface allowing the skin to maintain its water barrier functions
5 TBXAS1 (CYP5A1) is classified as CYP5A1 but is more commonly known as thromboxane A synthase 1; catalyzes the conversion of conversion of prostaglandin H2 to thromboxane A2 (TXA2)
7 CYP7A1, CYP7B1 CYP7A1 commonly called cholesterol 7α-hydroxylase, is the rate-limiting enzynme in the primary (classic) pathway of bile acid synthesis
CYP7B1 is also known as oxysterol 7α-hydroxylase; involved in the synthesis of bile acids via the less active secondary (acidic) pathway
8 PTGIS (CYP8A1), CYP8B1 CYP8A1 is prostaglandin I2 synthase encoded by the PTGIS gene; catalyzes the conversion of prostaglandin H2 to prostacyclin (PGI2)
CYP8B1 also known as sterol 12α-hydroxylase involved in bile acid synthesis
11 two subfamilies: A and B

CYP11A1, CYP11B1, CYP11B2
CYP11A1 mitochondrial enzyme commonly known as 20,22-desmolase or cholesterol side-chain cleavage enzyme (or P450ssc) which catalyzes the initial reaction of steroid hormone synthesis; converts cholesterol to pregnenolone; active enzyme is a complex CYP11A1, adrenodoxin reductase, and ferredoxin-1 (also known as adrenadoxin)
CYP11B1 mitochondrial enzyme commonly known as steroid 11β-hydroxylase; expressed in the zona fasciculata and zona glomerulosa of the adrenal cortex; involved in the synthesis of glucocorticoids and aldosterone
CYP11B2 mitochondrial enzyme more commonly called aldosterone synthase; only expressed in the zona glomerulosa of the adrenal cortex; converts corticosterone to aldosterone; activity is regulated by the renin-angiotensin system
17 CYP17A1 endoplasmic reticulum localized enzyme; possesses two distinct activities: steroid 17α-hydroxylase and 17,20-lyase; involved in steroid hormone synthesis; the 17α-hydroxylase activity converts pregnenolone to 17-hydroxypregnenolone, while the 17,20-lyase activity converts 17-hydroxypregnenolone to dehydroepiandrosterone (DHEA); expressed in the zona fasciculata and zona reticularis of the adrenal cortex where is is involved in the synthesis of glucocorticoids and androstenedione: expressed in the gonads where is is involved in sex hormone synthesis
19 CYP19A1 endoplasmic reticulum localized enzyme; commonly called aromatase or estrogen synthetase; involved in steroid hormone synthesis; primarily responsible for the aromatization of androgens in their conversion to estrogens; expressed at high level in the gonads but also expressed in adipose tissue, skin, and bone
20 CYP20A1  
21 CYP21A2 commonly called steroid 21-hydroxylase; expressed in the zona fasciculata and zona glomerulosa of the adrenal cortex; converts progesterone to 11-deoxycorticosterone and the conversion of 17-hydroxyprogesterone to 11-deoxycortisol; mutations in gene result in the most common forms of congenital adrenal hyperplasia (CAH)
24 CYP24A1 is a mitochondrial enzyme responsible for the degradation of 1,25-dihydroxyvitamin D3 (calcitriol)
26 three subfamilies: A, B, and C

CYP26A1, CYP26B1, CYP26C1
CYP26A1 can 4-hydroxylate and 18-hydroxylate the retinoids, in particular retinoic acid; important for regulating the intracellular levels of retinoic acid
CYP26B1 involved in the inactivation of all-trans-retinoic acid
CYP26C1 involved in the catabolism of retinoids such as all-trans- and 9-cis-retinoic acid
27 three subfamilies: A, B, and C

CYP27A1, CYP27B1, CYP27C1
CYP27A1 is also known as sterol 27-hydroxylase; involved in the diversion of cholesterol into bile acids via the secondary (acidic) pathway; hydroxylates numerous sterols at the 27 position
CYP27B1 is commonly known as 1α-hydroxylase or 25-hydroxyvitamin D3 1α-hydroxylase; expression is induced in renal tissue in reponse to the action of parathyroid hormone, PTH; converts 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 (calcitriol)
39 CYP39A1 also known as oxysterol 7α-hydroxylase 2; preferred substrate is 24-hydroxycholesterol which is a major product of CYP46A1
46 CYP46A1 also known as cholesterol 24-hydroxylase; expressed primarily in neurons of the central nervous system where it plays an important role in metabolism of cholesterol in the brain; 24S-hydroxycholesterol is a potent activator of LXR
51 CYP51A1 also known as lanosterol-14α-demethylase; catalyzes the removal of the 14α-methyl group from lanosterol in the cholesterol biosynthesis pathway; oxysterols derived through the action of CYP51A1 inhibit the rate-limiting enzyme in cholesterol synthesis, HMG-CoA reductase (HMGR)

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CYP Enzymes in Drug and Xenobiotic Metabolism

Therapeutic drugs are eliminated following administration via three primary mechanisms. These three mechanisms include renal excretion, CYP-mediated metabolism, and conjugation reactions that are predominantly glucuronidation reactions. Beginning in the early 1950s it was becoming apparent that the responses of different individuals to the same dose of the same drug could be profoundly different. Research began to show that the genetic make-up of an individual contributed significantly to therapeutic drug metabolism and the area of research became known as pharmacogenetics/pharmacogenomics. Given that the vast majority of therapeutic drugs are metabolized by the CYP family of enzymes, significant work has been devoted to an understanding of which CYP family member metabolizes which class, or classes, of drug (as well as other xenobiotics) and to what extent genetic differences (polymorphisms) play a role in individual responses and sensitivities to various drugs. Although several CYP enzymes are involved in drug metabolism, greater than 60% of therapeutic drugs are metabolized by CYP2C9, CYP2C19, CYP2D6, and CYP3A4.

Differences in the drug metabolizing activities of the same CYP enzyme in different individuals due to genetic polymorphisms result from increased, decreased, or absent expression and activity. These genetic differences allow individuals to be classified based upon their different CYP activity profiles. These classifications are related to a persons genotype such that individuals who express two wild-type copies of a particular CYP gene are termed extensive metabolizers. Individuals who express two variant alleles of a CYP gene leading to inactive or absent enzyme are referred to as poor metabolizers. Individuals classified as intermediate metabolizers are most often heterozygotes expressing one wild-type allele and one variant allele. Individuals who are ultrarapid metabolizers possess more than two alleles (gene duplication or amplification) of a particular CYP gene. Gene duplication has only been shown to be associated with the CYP2D6 gene. The variant alleles of the CYP genes are identifed by the inclusion of an asterisk followed by a number designating the particular polymorphism. For instance variant CYP2D6 genes are designated CYP2D6*1 etc.

CYP2D6 is a major therapeutic drug metabolizing enzyme accounting for the elimination of nearly 25% of all drugs with its substrates being primarily lipophilic bases. The list of drugs metabolized by CYP2D6 is well beyond the scope of this discussion but includes the hypertensive drugs of the beta blocker class, numerous antidepressants (such as the tricyclic antidepressants and the selective serotonin reuptake inhibitors, SSRIs) and antipsychotics, anti-cancer drugs (in particular the vinca alkaloids), opioids (in particular codeine), amphetamine, and the cough suppressant dextromethorphan to mention a few key examples. As indcated in the Table above, at least 160 different polymorphisms have been identified in the CYP2D6 gene resulting in all four classifications of individuals; ultra metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers. As indicated CYP gene variants are designated with an asterisk and number. With respect to the CYP2D6 gene the CYP2D6*2 variants represent the copy number variant and individuals can have 1, 2, 3, 4, 5, or 13 copies of the gene. In contrast the CYP2D6*3, *4, and *5 variants epxress an inactive enzyme or do not produce a protein at all. These CYP2D6 variants are the ones that are most commonly implicated in the poor metabolizer phenotype. Ethnic variation is also significant with respect to CYP2D6 variants. For example, the CYP2D6*4 allele is the most common variant of this gene in the Caucasian population but in Chinese this variant is essentially non-existent. In contrast, the CYP2D6*10 variant represent almost 50% of the CYP2D6 alleles in Chinese but is essentially absent in Caucasians.

CYP2C9 is another major therapeutic drug metabolizing enzyme and represents as much as 35% of the total hepatic cytochrome P450 content. CYP2C9 is oinvolved in the metabolism of more than 100 different therapeutic drugs the coumarin (e.g. warfarin) anticoagulants, non-steroidal antiinflammatories (NSAIDs), and the anti-diabetic sulfonyureas being the most clinically relevant examples. There are over 60 classified CYP2C9 variants with the CYP2C9*2 and CYP2C9*3 variants having the most clinical significance. The rate of drug clearance in individuals harboring the CYP2C9*3 allele is the lowest of all CYP2C9 variants and this variant is found in roughly 10% of Caucasians. There are three coumarin family anticoagulants prescribed in the US with warfarin being the most prevalent. Warfarin (as well as acenocoumarol and phenprocoumon) exist in two chemical form (enantiomers) where the S-enantiomer is the most potent and is also the substrate for CYP2C9. Both of the major CYP2C9 variants (CYP2C9*2 and CYP2C9*3) cause reduced warfarin clearance and as such, individuals expressing these variants require a reduced dose of the drug relative to CYP2C9 wild-type expressing individuals. The role of CYP2C9 variants in the treatment of the hyperglycemia of type 2 diabetes (T2D) is extremely important. Common treatment of T2D involves the use of oral sulfonylureas (e.g. tolbutaminde or glyburide) which are insulin secretagogues. Individuals with the CYP2C9*3 allele metabolize the sulfonylureas at a rate that is less than 20% of individuals expressing the wild-type CYP2C9 gene. Therefore, these CYP2C9*3 individuals can suffer from severe hypoglycemia when taking a dose of a sulfonylurea that is equivalent to that taken by a wild-type individual.

Although CYP2C19 shares greater than 90% sequence identity with CYP2C9, the two enzymes exhibit distinct activity profiles and substrate specificities. At least 35 different types of CYP2C19 alleles have been identified. The CYP2C19*2 through CYP2C19*8 alleles are all associated with reduced enzymatic activity. The CTP2C19*17 allele is associated with ultrarapid metabolism. One of the most significant therapeutic drugs metabolized by CYP2C19 are the proton pump inhibitors (PPIs). Worldwide the PPIs represent some of the most extensively used drugs. Greater than 90% of omeprazole, lansoprazole, and pantoprazole is metabolized by CYP2C19. The remaining metabolism occurs via the action of CYP3A4. In addition to PPI metabolism CYP2C19 metabolizes benzodiazepines, tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI), barbiturates, and the antiepileptic drug phenytoin.

The majority of therapeutic drug and xenobiotic metabolism occurs via the activities of CYP enzymes in the liver. However, clinically significant xenobiotic metabolism does occur via the action of CYP enzymes in other tissues and organs with particular relevance being associated with their metabolism in the gastrointestinal system and the respiratory system. With respect to non-hepatic drug metabolism, the expression patterns of CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2S1, CYP3A4, CYP3A5, and CYP4B1 are the most significant.

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CYP Enzymes Involved in Lipid Homeostasis

Numerous CYP family member genes express enzymes that are involved in overall lipid homeostasis. These various enzymes are involved in the metabolism of sterols (including cholesterol and bile acids), fatty acids, and eicosanoids.

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Michael W King, PhD | © 1996–2017 themedicalbiochemistrypage.org, LLC | info @ themedicalbiochemistrypage.org

Last modified: April 6, 2017