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Association of Cytochrome P450 with Cancer Induced by Betel Quid (BQ): a Review Aniket Adhikari* and Madhusnata De

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Association of Cytochrome P450 with Cancer Induced by Betel Quid (BQ): a Review Aniket Adhikari* and Madhusnata De American Journal of Pharmacology and Pharmacotherapeutics Review Article Association of Cytochrome P450 with Cancer Induced by Betel Quid (BQ): A Review Aniket Adhikari* and Madhusnata De Department of Genetics, Vivekananda Institute of Medical Sciences, Ramakrishna Mission Seva Pratishthan 99, Sarat Bose Road , Kolkata – 700026, India *Corresponding author e-mail: [email protected] A B S T R A C T Betel quid (BQ) products have been classified by the International Agency for Research on Cancer (IARC) as group I human carcinogens that are associated with an elevated risk of oral potentially malignant disorders (OPMDs) and cancers of the oral cavity and pharynx and others. The human genome encodes fifty-seven cytochrome P45O (P45O, or CYP) proteins. The majority of these are involved in the metabolism of steroids, bile acids, fatty acids and xenobiotic compound which activate carcinogens. The present review focuses on the mechanism of CYP450 with betel quid which induces cancer. Keywords: Betel quid, Cancer, Cytochrome P450. INTRODUCTION Cytochrome P450 in general produced an unusual absorption peak at a The term cytochrome P450 was wavelength of 450 nm. Cytochrome P450 coined in 1962 as a temporary name for a (CYP450) is the generic name given to a coloured substance in the cell1. At first, large family of versatile enzymes that CYP450 was believed to represent a single metabolise most drugs and chemicals of enzyme. Today it seems likely that humans toxicological importance (termed xenobiotic and other mammals have approximately 50 metabolism). Along with xenobiotic distinct CYP450 enzymes. The total number metabolism, many CYP450 enzymes play may be higher in plants. In the last 15 years pivotal roles in diverse physiological of the 20th century, research was largely processes including steroid and cholesterol concerned with defining CYP450 biosynthesis, fatty acid metabolism multiplicity in humans and a diverse range (prostacyclin, thromboxane) and the of other organisms. This pigment, when maintenance of calcium homoeostasis. reduced and bound with carbon monoxide, American Journal of Pharmacology and Pharmacotherapeutics www.pubicon.in Adhikari et al_________________________________________________ ISSN 2393-8862 Cytochrome P450 enzyme (P450, or b5 (CYB5) can also contribute reducing CYP) reactions were first recognized in the power to this system after being reduced oxidation of drugs, carcinogens, and by the cytochrome b5 reductase steroids, and generally show the mixed- (CYB5R). function oxidase stoichiometry: Mitochondrial P450 systems, those + + NADPH+H + R+O2→NADP + H2O+RO. employ adrenodoxin reductase and (R = substrate, RO = product). adrenodoxin to transfer electrons from In mammals, all P450s are NADPH to P450. membrane bound, most are found in the Bacterial P450 systems, that employ a endoplasmic reticulum, but five are ferredoxin reductase and a ferredoxin to localized primarily in mitochondria2. The transfer electrons to P450. human genome encodes fifty-seven P450 CYB5R/cyb5/P450 systems in which proteins3. A recent survey classified fifteen both electrons required by the CYP come P450s involved in the metabolism of from cytochrome b5. xenobiotic chemicals (i.e., chemicals, such FMN/Fd/P450 systems are originally as drugs, not normally found in the body): found in the Rhodococcus sp. fourteen primarily involved in the A subset of cytochrome P450 enzymes metabolism of sterols (including bile acids); play important roles in the synthesis four that oxidize fat-soluble vitamins; and of steroid hormones (steroidogenesis) by nine involved in the metabolism of fatty the adrenals, gonads, and peripheral acids and eicosanoids4. Substrates (either tissue: xenobiotic and endobiotic) are essentially CYP11A1 (also known as P450scc or unknown for the remaining fifteen of the P450c11a1) in adrenal mitochondria fifty-seven. P450s are found throughout the effects “the activity formerly known as phylogenetic spectrum: three have been 20, 22-desmolase” (steroid 20α- identified in Saccharomyces cerevisiae, hydroxylase, steroid 22-hydroxylase, eighteen in Streptomyces coelicolor, eighty cholesterol side-chain scission). in Caenorhabiditis elegans, 257 in CYP11B1 (encoding the protein Arabidopsis thaliana, and perhaps P450c11β) is found in the inner surprisingly, none in Escherichia coli or mitochondrial membrane of adrenal Salmonella typhimurium. cortex has steroid 11β-hydroxylase, CYP enzymes have been found in all steroid 18-hydroxylase, and steroid 18- domains of life such as animals, plants, methyloxidase activities. fungi, bacteria, and even in viruses5. But the CYP11B2 (encoding the protein enzymes have not been found in E. coli6,7. P450c11AS) is found only in the More than 18,000 distinct CYP proteins are mitochondria of the adrenal. It has steroid known8. Most CYPs require a protein partner 11β-hydroxylase, steroid 18-hydroxylase, to deliver one or more electrons to reduce the and steroid 18-methyloxidase activities. iron (and eventually molecular oxygen). CYP17A1, in endoplasmic reticulum of Based on the nature of the electron transfer adrenal cortex has steroid 17α- proteins CYPs can be classified into several hydroxylase and 17, 20-lyase activities. groups9:- CYP21A1 (P450c21) in adrenal cortex Microsomal P450 systems in which conducts 21-hydroxylase activity. electrons are transferred from NADPH CYP19A (P450arom, aromatase) in endo- via cytochrome P450 reductase (variously plasmic reticulum of gonads, brain, CPR, POR, or CYPOR). Cytochrome AJPP[2][1][2015] 081-094 Adhikari et al_________________________________________________ ISSN 2393-8862 adipose tissue, and elsewhere catalyzes Cytochrome P450cam (CYP101) aromatization of androgens to estrogens. originally from Pseudomonas putida has been used as a model for many CYP families in humans cytochromes P450 and was the first Humans have 57 genes and more than cytochrome P450 three-dimensional 59 pseudogenes divided among 18 families of protein structure solved by X-ray cytochrome P450 genes and 43 subfamilies10. crystallography. This enzyme is part of a This is a summary of the Cytochrome P450 camphor-hydroxylating catalytic cycle family with their functions:- (See table 1.) consisting of two electron transfer steps from putidaredoxin, a 2Fe-2S cluster- P450s in other species containing protein cofactor. Cytochrome P450 eryF (CYP107A1) Animals originally from the actinomycete Many animals have as many or more bacterium Saccharopolyspora erythraea is CYP genes than humans do. For responsible for the biosynthesis of the example, mice have genes for 101 CYPs, antibiotic erythromycin by C6- and sea urchins have even more (perhaps as 11 hydroxylation of the macrolide 6- many as 120 genes) . deoxyerythronolide B. CYPs have been extensively examined in the mice, rats, dogs, and less so Fungi in zebrafish, in order to facilitate use of The commonly used azole class these model organisms in drug discovery antifungal drugs work by inhibition of the and toxicology. Recently CYPs have also fungal cytochrome P450 14α-demethylase. been discovered in avian species, in particular This interrupts the conversion of lano turkeys, that may turn out to be a great model 12 sterol to ergo sterol, a component of the for cancer research in humans . CYP1A5 fungal cell membrane. (This is useful only and CYP3A37 in turkeys were found to be because humans' P450 have a different very similar to the human CYP1A2 and sensitivity; this is how this class CYP3A4 respectively, in terms of their of antifungals work)16. kinetic properties as well as in the metabolism 13 of aflatoxin B1 . Plants CYPs have also been heavily studied Plant cytochromes P450 are involved in insects, often to understand pesticide in a wide range of biosynthetic reactions, resistance. For example, CYP6G1 is linked to leading to various fatty acid conjugates, plant insecticide resistance in DDT-resistant 14 hormones, defensive compounds, or Drosophila melanogaster and CYP6Z1 in medically important drugs. the mosquito malaria vector Anopheles gambiae is capable of directly metabolizing 15 CYP’S related with cancer DDT . Experimental models have clearly demonstrated that the modulation of P450 Microbial expression can modify the susceptibility of Microbial cytochromes P450 are often animals to cancers produced by various soluble enzymes and are involved in critical chemicals17,18. The relevance of P450 metabolic processes. Three examples that modulation to cancer risk has not been easy to have contributed significantly to structural establish in humans, however. Nonetheless, in and mechanistic studies are listed here, but vitro studies have largely established that many different families exist. AJPP[2][1][2015] 081-094 Adhikari et al_________________________________________________ ISSN 2393-8862 human P450s can activate most major aromatic hydrocarbons (PAHs), into highly chemical carcinogens19-21. The main P450s reactive intermediates38. When these involved in carcinogen activation appear to be compounds bind to DNA and form adducts, CYP1A1, CYP1A2, CYP1B1, CYP2A6, they may contribute to carcinogenesis. The CYP2E1, and CYP3A4, with some aromatic hydrocarbon receptor is a key contributions from CYP4B122 and CYP2A13 activator of the CYP1A1 gene39,40. PAHs also possible23,24. Another set of studies on were classified among important toxicants as lung cancer investigated CYP2D6 and a they induce CYP1A1 gene and act as pre possible reduced risk in smokers with the carcinogenic substrates41,42. Asignificant
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