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American Journal of Pharmacology and Pharmacotherapeutics

Review Article Association of P450 with 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 that are associated with an elevated risk of oral potentially malignant disorders (OPMDs) and of the oral cavity and pharynx and others. The encodes fifty-seven cytochrome P45O (P45O, or CYP) . The majority of these are involved in the of , bile acids, fatty acids and compound which activate carcinogens. The present review focuses on the mechanism of CYP450 with betel quid which induces cancer.

Keywords: Betel quid, Cancer, .

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 that CYP450 was believed to represent a single metabolise most drugs and chemicals of . 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 and concerned with defining CYP450 biosynthesis, 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,

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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 = , 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 , 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 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. (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- activities. groups9:-  CYP21A1 (P450c21) in adrenal cortex  Microsomal P450 systems in which conducts 21-hydroxylase activity. electrons are transferred from NADPH  CYP19A (P450arom, ) in endo- via cytochrome P450 reductase (variously plasmic reticulum of gonads, brain, CPR, POR, or CYPOR). Cytochrome

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adipose tissue, and elsewhere catalyzes  Cytochrome P450cam (CYP101) aromatization of androgens to . originally from Pseudomonas putida has been used as a model for many CYP families in humans P450 and was the first Humans have 57 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 .  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, 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 drugs work by inhibition of the and toxicology. Recently CYPs have also fungal cytochrome P450 14α-. 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 work)16. kinetic properties as well as in the metabolism 13 of 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 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 and act as pre possible reduced risk in smokers with the carcinogenic substrates41,42. Asignificant poor metabolizer phenotype25. CYP2E1, association between metabolizing phase I known to activate many carcinogens26 with genes (CYP1A1) and UADT cancers was cancers27,28 suspected association between found43. Nagaraj et al.44 identified molecular CYP3A4 and prostate cancer29 has not been factors which contribute to the increased risk reproducible30-32. Some of the best current of smokers for oral squamous cell carcinoma candidates are CYP1A2 and CYP2A6. (OSCC). In fact, they evaluate gene CYP1A2 activates many heterocyclic amines expression profile change according to present in pyrrolyzed food, especially charred cigarette smoke condensate in normal meat. Epidemiological studies have shown epidermal keratinocytes, oral dysplasia cell increased risk of colon cancer in individuals lines Leuk1 and Leuk2, and a primary oral with high CYP1A2 activity. CYP2A6 carcinoma cell line 101A. Their results have activates some nitrosamines and is expressed shown that treatment by cigarette smoke in the head and neck; a cancer risk may thus condensate acts on several cell types and be associated with higher expression of usually leads to over expression of CYP1A1. CYP2A624. A study by Kamataki and Several studies have been since performed colleagues associated a poor metabolizer examining the potential association between genotype with decreased risk of lung cancer the polymorphic CYP1A1. The CYP1A1 in Japan33. One factor in the analysis, (426Val/Val) genotype was found three times however, may be a tendency for smokers more frequent than in controls in 3% of oral deficient in CYP2A6 to smoke less because cancer patients. In spite of the absence of any of its involvement in metabolism34. statistical significance, these results strongly Two other candidates possibly connected with supported the previous ones showing that the cancer include CYP1B1 and CYP2A13. mutant allele CYP1A1 426Val is related to an CYP1B1 is expressed in several organs and increased risk of oral cancer in Caucasians, in tissues (e.g., breast, prostate, and ovary) and the United States45, among Asian activates numerous carcinogens in vitro35. populations46, and in Indians47. Cigarette The 4-hydroxylation activity of smoke has been shown to upregulate CYP1B1 is of particular interest with regard CYP1A1 under in vitro conditions as well as to estrogen-responsive tumors36,37. CYP2A13, in smokers48,49. In five earlier different studies which is similar to CYP2A6, activates investigating CYP1A1 genotype smoking nitrosamines and is localized in tissues of the interactions50-54 CYP1B1. Human CYP1B1 is respiratory tract23,24. located on 2 at the 2p21-22 region55,56. CYP1B1 gene is activated by CYP1A1 PAHs that constitute the major constituents of The human enzyme CYP1A1 is the cigarette smoke and , hence making it most active among the CYPs in metabolizing responsive to smoked and smokeless procarcinogens, particularly, the polycyclic (chewing) tobacco55,57,58. As CYP1B1 is

AJPP[2][1][2015] 081-094 Adhikari et al______ISSN 2393-8862 crucially involved in the bioactivation of oral mucosa, and in tongues of rats75,76. chemically diverse tobacco-related Association of the CYP2E1 polymorphism procarcinogens to reactive metabolites, its with the risk of lung cancer77, gastric expression is considered as a significant cancer78,79 and pancreatic cancer80 . CYP2E1 parameter of carcinogenesis59. CYP1B1 is metabolizes and generates reactive over expressed in several human tumors in oxygen species, and it has been suggested that comparison with normal tissues58,60,61. it is important for the development of CYP1B1 in modulating the incidence alcoholic liver disease and cancer, including of several types of cancers62,63. CYP1B1 with hepatoblastoma and HNC. the increased risk of ovarian, endometrial, renal, and prostate cancers as well as smoking Cancer production due to betel quid related lung cancer has been reported in the Betel quid chewing habit (betel leaf, Caucasian and the Japanese populations64. areca nut and lime) in India are at least 2,000 CYP1B1 is upregulated in numerous cancers years old. Tobacco was introduced around the such as esophagus, lung, skin, breast, brain, sixteenth century. It is estimated that at least testis, and colon cancers65. 200 million individuals consume areca nuts in one form or another worldwide. The habit is CYP2D6 now widespread in Southeast Asia and the The CYP2D6 gene is localized on South Pacific islands and in people of Indian chromosome 22q13.166.Cytochrome P450s origin elsewhere in the world. The betel quid consist of the major enzymes required for chewing habit is in fact found all over the phase I metabolism of . world wherever Indians have settled. The BQ Cytochrome P450 2D6 (CYP2D6) is one of is a mixture of areca nut (Areca catechu), the enzymes that catabolize about 20% of catechu (Acacia catechu) and slaked lime commonly prescribed drugs. Cytochrome (calcium oxide and calcium hydroxide) P450 2D6 has also a variety of activities wrapped in a betel leaf (Piper betle). Betel nut among human populations. In fact, the is composed of 11.4% – 26.0% tannins, 0.15 - interindividual metabolism rates differ more 0.67% alkaloid, 1.3 -17% fat, 0.13 -2.35% than 10000 folds66-69. CYP2D6 gene is phosphorus, 1.5 -11.6% iron81. The major activated by some xenobiotic carcinogens areca nut alkaloids are arecoline, arecaidine, such as nicotine which is the major arecolidine, guvacoline and guacine82. constituent of tobacco70. Arecoline (1, 2, 4, 5-tetrahydro-1- methylpyridinecarboxylic acid; molecular CYP2E1 weight 155.19) is the most abundant alkaloid The CYP2E1 human gene is located of areca. These alkaloids undergo nitrosation on chromosome10 (10q24.3-qter), contains 9 and give rise to N-nitrosamines83. Chewers of exons, and encompasses several BQ with or without tobacco often develop polymorphisms. Some of them have an effect clinically visible whitish (leukoplakia) or on the protein expression71. The CYP2E1 reddish (erythroplakia) lesions and/or enzyme is responsible for the metabolism of stiffening of the oral mucosa and oral and some tobacco carcinogens such as submucous fibrosis (OSF). Leukoplakia is low-molecular weight nitrosamines72-74. one of the commonest lesions in betel quid CYP2E1 enzyme activity is needed during the chewers. The WHO has classified these into metabolic activation of many carcinogens two groups, homogeneous and non- such as nitrosamines. CYP2E1 is expressed in homogeneous. Among no homogeneous oral epithelial cell lines cultures, in human leukoplakias, nodular leukoplakia tends to

AJPP[2][1][2015] 081-094 Adhikari et al______ISSN 2393-8862 show the highest rate of malignant when they react with available nitrite in the transformation. The relative risk compared presence of catalysts such as thiocyanate91,92. with individuals with tobacco habits but Using a modified N-nitrosoproline (NPRO) without any precancerous oral lesion was also test96, it was clearly shown that NPRO, a found to be the highest for nodular marker of endogenous nitrosation, is formed leukoplakia84. Oral sub mucous fibrosis during chewing of BQ92. Elevated levels of (OSMF) is a chronic condition characterized nitrite and nitrate reductase activity have been by mucosal rigidity of varying intensity due to reported in the saliva of Indian chewers of BQ fibro elastic transformation of the juxta with tobacco97. There is increased nitric oxide epitheliallayer85. Areca nut chewing could be and nitrite formation in subjects during one of the most important etiologic factors in deposition of dental plaque98. OSMF86. The areca nut, the major constituent Many chewers swallow the quid that of pan masala is responsible for mutagenic, contains precursors of nitrosamines. The clastogenic and carcinogenic properties87. acidic pH of the stomach would favour the Chewing of tobacco with BQ results in high nitrosation of secondary and tertiary amines exposure to carcinogenic tobacco-specific in the quid. Detection of NG and its nitrosamines (TSNAs), to ~1000 mg/day88, metabolite Nnitrosonipecotic acid in the urine compared with ~20 mg/day in smokers89, as of Syrian hamsters fed areca nut and well as leading to exposure to nitrosamines nitrite99,100 also supports the notion that derived from areca nut alkaloids. The exposure to carcinogenic nitrosamines formed carcinogenic TSNAs N’- nitrosonornicotine by endogenous nitrosation is likely to be (NNN), 4-(N-methyl-N-nitrosamino)-1- (3- higher in BQ chewers who swallow the quid. pyridyl)-1-butanone (NNK) and N- nitrosoanabasine (NAB), as well as the Relation with betel quid and CYPs volatile nitrosamines N-nitrosodimethylamine Cytochrome P450s regulate the and N-nitrosodiethylamine, have been expression of enzymes that convert detected in the saliva of chewers of BQ with procarcinogens to their ultimate carcinogenic tobacco90-93. The areca nut-specific forms101,102. The nitrosation of arecoline, nitrosamines (ASNAs) N-nitrosoguvacoline which contains a 3- ethylenic bond at the 3-4 (NG)90-92,94 and the carcinogenic 3-(methyl- position on the pyridinium ring, may produce N-nitrosamino) propionitrile (MNPN)95 were a variety of betel-nut-specific nitrosoamines also detected in the saliva of chewers of BQ (BSNA). Although cytochrome p450 without tobacco(Table II). ASNAs were not CYP2D6, CYP1A1 and CYP2E1 loci have detected in BQ containing areca nut. been examined for oral cancer patients and Nitrosation of BQ with nitrate and control individuals, there are no differences thiocyanate in vitro at neutral pH resulted in between them in the frequencies of presumed the formation of NG91. Presence of ASNAs in risk genotypes103. the saliva of BQ chewers could arise from CYP2A6 was found to be the most their formation during chewing of BQ. The efficient activator of 3-methylnitrosamino highest levels of an ASNA (NG) were found propionitrile (MNPN) followed by CYP1A1, in the sediment of saliva collected from and N-nitrosoguvacoline (NGL), was Taiwanese BQ chewers94, whereas the highest activated by CYP2A6. The genotoxicity of levels of TSNAs have been found in saliva NGL was observed to be substantially lower samples collected in India 93. Secondary and than that of MNPN or 3-methylnitrosamino tertiary amines present in areca nut and propionaldehyde (MNPA)104. CYP1A1 tobacco can be nitrosated during BQ chewing Exon7 polymorphism G/G genotypes are

AJPP[2][1][2015] 081-094 Adhikari et al______ISSN 2393-8862 susceptible to BQ-related oral cancer and 2. H.K. Anandatheerthavarada, C. OPMDs105. Human CYP2A and CYP2E Vijayasarathy, S.V. Bhagwat et al., subfamily members play important roles in “Physiological role of the Nterminal the metabolic activation of arecoline-related processed P4501A1 targeted to N-nitrosamines106-108. Located on human mitochrondria in erythromycin metabolism and reversal of erythromycin-mediated , CYP2A express at least 13 inhibition of mitochondrial protein different isoenzymes, among which CYP2A6 synthesis” , J. Biol. Chem,1999, 274, 6617– metabolically activates the N- 6625. alkylnitrosamines, N-nitrosonornicotine, and 3. D.R. Nelson. “Comparison of P450s from 4- (methylnitrosamino) - 1 - (3-pyridyl) - 1 - human and fugu: 420 million years of butanone, which have relatively long alkyl vertebrate P450 evolution”, Arch Biochem chains109,110. Miyazaki et al. first reported that Biophys, 2003, 409, 18–24. CYP2A subfamilies play important roles in 4. F.P. Guengerich. “New overview of the mutagenic activation of AN-derived N- distribution,substrates, inhibitors, active nitrosamines104. sites,and clinical relevance of the fifty seven human P450s.Human cytochrome P450 enzymes”, In Cytochrome P450,3rd. Edn. CONCLUSION (ed. Ortiz de Montellano, P.R.) Plenum Betel chewing is popular habit in Press, New York, 2003, in press.

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Table 1. CYP their families, name and their functions

Family Function Members Names

Drug and steroid (especially 3 subfamilies, 3 genes, 1 CYP1 estrogen) metabolism, benzo (a) CYP1A1, CYP1A2, CYP1B1 pseudogene pyrene toxification CYP2A6, CYP2A7, CYP2A13, CYP2B6, 13 subfamilies, 16 CYP2C8, CYP2C9,CYP2C18, CYP2C19, CYP2 Drug and steroid metabolism genes, 16 pseudogenes CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2R1, CYP2S1, CYP2U1, CYP2W1 Drug and steroid (including 1 subfamily, 4 genes, 2 CYP3 CYP3A4, CYP3A5, CYP3A7, CYP3A43 testosterone) metabolism pseudogenes CYP4A11, CYP4A22, CYP4B1, CYP4F2, CYP4 or fatty acid 6 subfamilies, 12 genes, CYP4 F3, CYP4F8,CYP4F11, CYP4F12, CYP4F22, C metabolism 10pseudogenes YP4V2, CYP4X1, CYP4Z1

CYP5 thromboxane A2 synthase 1 subfamily, 1 gene CYP5A1 bio synthesis 7-alpha CYP7 2 subfamilies, 2 genes CYP7A1, CYP7B1 hydroxylase of steroid nucleus CYP8A1 (), CYP8B1 CYP8 Varied 2 subfamilies, 2 genes (bile acid biosynthesis) CYP11 Steroid bio synthesis 2 subfamilies, 3 genes CYP11A1, CYP11B1, CYP11B2 Steroid bio synthesis, 17-alpha

CYP17 1 subfamily, 1 gene CYP17A1 hydroxylase Steroid biosynthesis:aromatase

CYP19 synthesizes 1 subfamily, 1 gene CYP19A1 estrogen

CYP20 Unknown function 1 subfamily, 1 gene CYP20A1 Steroid bio 2 subfamilies, 1 gene, 1

CYP21 CYP21A2 synthesis pseudogene

CYP24 degradation 1 subfamily, 1 gene CYP24A1 Retinoic acid CYP26 3 subfamilies, 3 genes CYP26A1, CYP26B1, CYP26C1 hydroxylase CYP27A1 (bile acid biosynthesis), CYP27B1 (vitamin D 1- CYP27 Varied 3 subfamilies, 3 genes 3 alpha hydroxylase, activates vitamin

D3), CYP27C1 (unknown function) 7-alpha hydroxylation of 24-

CYP39 1 subfamily, 1 gene CYP39A1 hydroxycholesterol

CYP46 Cholesterol 24-hydroxylase 1 subfamily, 1 gene CYP46A1

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