Critical review CYP1B1: friend or foe? A critical

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Enzymology

Critical review CYP1B1: friend or foe? A critical review

Abstract Introduction Cytochrome P450 1B1 is one of the main extra-hepatic cytochromes and has been investigated for its ability to metabolize both exogenous and endogenous compounds into their carcinogenic derivatives. These derivatives are linked to cancer initiation and progression. The compound 7,12-dimethylbenz(a) anthracene (DMBA) is possibly the most investigated polycyclic aromatic hydrocarbon available, besides benzo-a-pyrene, and it has been shown that in vivo cytochrome P1B1, and not cytochrome P1A1, is the main enzyme in the metabolic activation of 7,12-dimethylbenz(a) anthracene to carcinogenic metabolites. Cytochrome P1B1 has also been implicated in drug resistance as well as in angiotensin-induced hypertension, which can subsequently lead to renal failure. For decades, inhibitors of this enzyme have been deemed chemoprotective and, more recently, anti-hypertensive. On the other hand, elevated levels of cytochrome P1B1 in cancerous tissues relative to normal neighbouring ones have been deemed a new mechanism for cancer treatment with the use of pro-drugs. This review will take an in-depth and critical look at both regiments of cytochrome P1B1. Conclusion More research is necessary to determine whether the carcinogenic properties of cytochrome P1B1 will

*Corresponding author Email: [email protected] Natural Products Institute, Faculty of Science and Technology, University of the West Indies, Mona, Kingston 7, Jamaica, West Indies

outweigh its possible chemotherapeutic applications.

Introduction Cancer is a multistep process, which involves the initiation, promotion and progression of abnormal cellular growth that can arise from the route of carcinogenesis or inherited abnormal genes. Till date it is not known which one of the two plays a greater role, but there is evidence linking both factors to the initiation and progression of cancer. Given that cancer is the third leading cause of death worldwide1, it attracts large global collaborative efforts with an aim to increase the knowledge about it and treatment options. The process of carcinogenesis occurs when normal cells are transformed into malignant ones that recurrently divide to become a cancer. Cancer initiation via this mechanism can ensue from chemicals, viruses or radiation, which would be deemed carcinogens collectively. Understanding the mechanism of carcinogenesis can ultimately not only provide treatment options for cancer but preventative ones as well. The latter angle is known as chemoprevention, which is the process of protecting healthy tissues by preventing, inhibiting or reversing the process of carcinogenesis and this can be achieved by various mechanisms. These include the induction of cell cycle arrest2; the induction of phase II enzymes, such as Glutathione S-transferase, Methyl transferases and Arylamine-N-acetyl transferases3; the inhibition of in lammatory agents such as pro-in lammatory cytokines, COX-2 and Inos4; and the inhibition of cytochrome P450 (CYP450) enzymes5 (Figure 1).

CYP450 enzymes are phase I drug metabolizing enzymes whose primary catalytic mode of action is a mono-oxygenase reaction, though they also catalyse a surfeit of other reactions6. Of the 18 mammalian families known, the CYP1 family (CYPs 1A1, 1A2 and 1B1) has been most implicated in reactions resulting in highly mutagenic compounds7, as their involvement in metabolizing polycyclic aromatic hydrocarbons (PAHs) has been well researched8,9. The association of CYP1B1’s activity in the initiation of several human cancers via this mechanism has been well documented10,11 resulting in inhibitors of this enzyme being deemed potential chemoprotectants. More recent research has found elevated levels of CYP1B1 in cancer tissues relative to normal neighbouring ones11; this is believed to play a role in chemotherapeutic drug resistance. When a patient fails to respond to a particular therapy, this can be as a result of host factors (poor absorption, rapid metabolism or excretion of a drug) or speci ic genetic changes in tumour cells12. The elevated levels of CYP1B1 in tumour cells have been associated with host-factor drug resistance since it is also involved in the metabolism of selected chemotherapeutic drugs such as docetaxel resulting in reduced cytotoxicity towards these cells. On the other hand, because of the elevated levels of this enzyme in cancerous tissues relative to normal neighbouring ones11, the recent understanding is this could be the answer to better cancer treatment. This review will analyse the involvement CYP1B1 in cancer initiation, the successes of CYP1B1 inhibitors in preventing or slowing down this

Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY) F

: Badal S, Delgoda R. CYP1B1: friend or foe? A critical review. OA Biochemistry 2013 Apr 01;1(1):8.

CompeƟng interests: none declared. Conflict of interests: none declared. All authors contributed to the concept on, design, and preparaƟon of the manuscript, as well as read and approved the final manuscript. All authors abide by the AssociaƟon for Medical Ethics (AME) ethical rules of disclosure.

S Badal*, R Delgoda

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Critical review

PRO-CARCINOGEN

1 CELL CYCLE

HEALTHY CELL

INFLAMMATORY AGENTS: PROINFLAMMATORY CYTOKINES, COX-2, iNOS

3

4

CANCER

CYTOCHROME P450: CYPs 1A1, 1A2, & 1B1

1

Chemoprevention via Cell Cycle Arrest

2

Chemoprevention via Detoxification

3

Chemoprevention via suppressing Angiogenesis and Immune Suppression

4

Chemoprevention via inhibition of Carcinogenesis

Up-regulation/ Induction Down-regulation/Inhibition

Figure 1: A schematic representation of chemoprevention displaying various contributing factors using chemoprevention. The upregulation/induction of the cell cycle, pro-in lammatory agents and CYPs1A1, 1A2 and 1B1 contributes to the formation of cancer cells and the reverse contributes to normal cell formation. The downregulation/inhibition of phase II enzymes contributes to cancer cell formation and the reverse contributes to normal cell formation. process as well as the potential role of this enzyme in tissue-speci ic cancer treatment.

Discussion The authors have referenced some of their own studies in this review. The protocols of these studies have been approved by the relevant ethics committees related to the institutions in which they were performed. Despite more than 20 years of research on the CYP1 family, CYP1B1 was not identi ied and sequenced until 1994. CYP1B1 was identi ied

in rodent species and in humans13,14 and is primarily expressed in human lung15. Its critical role in the conversion of several PAHs is mainly due to catalysis of the aromatic ring, which undergoes hydroxylation reaction(s) at a vacant position. The most documented PAHs metabolized by CYP1B1 is 7,12-dimethylbenz(a)anthracene (DMBA), the catalysis of which is shown in Figure 2. The recurrent and concretized association of PAHs in the process of carcinogenesis can be explained by their transcriptional regulation being controlled by the aryl hydrocarbon

receptor (AhR). In its inactivated state, the AhR is associated with heat-shock protein 90 (HSP-90) homodimer16, a p23 chaperone17 and an immunophilin-related protein XAP-218 in the cytosol. Upon binding to the AhR, aryl hydrocarbons trigger the dissociation of coupled proteins after which the complex (AhRligand) is translocated to the nucleus. Once in the nucleus, the AhRligand complex binds to the AhR nuclear translocator (ARNT), which then subsequently binds to the xenobiotic response element (XRE). XRE is a cassette of speci ic DNA sequences,




PHASE II ENZYMES: NAT, GST, MT etc

2

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Critical review

3,4 diol-DMBA

DMBA

7-OHM-12MBA

Highly mutagenic

3,4 diol-DMBA

5,6 diol-DMBA

8,9 diol-DMBA 8

Not highly mutagenic

10,11 diol-DMBA

7-hydroxymethyl-12-methylbenzanthracence (7-OHM-12MBA) 7,12-dimethylbenz(a)anthracene (DMBA) 1,2-epoxide-3,4-diol-DMBA

Figure 2: A schematic representation of different metabolites formed from DMBA.

CYP1A1

17-β estradiol

16-OH-E Binds covalently to: • oestrogen receptor • histones • DNA

CYP1B1 4-OH-E

CYP1A1 2-OH-E

Antagonist of the oestrogen receptor “the good oestrogen”

16-hydroxy Estradiol (16-OH-E) 4-hydroxy-Estradiol (4-OH-E) 2-Hydroxy-Estradiol (2-OH-E)

Figure 3: Several oestrogen metabolites formed from the action of CYP enzymes. more vulnerable to its effect, especially if she works in an environment that puts her in constant exposure to such PAHs.

Not only is CYP1B1 involved in carcinogenesis, it is also involved in the metabolism of several chemotherapeutic drugs and, by extension,




which is upstream; various genes, such as CYP1B1, trigger the transcription of these19. The upregulation of the CYP1 enzymes in turn results in increased metabolism of pro-carcinogens producing more metabolites, including ultimate carcinogens6. Widely used as a model chemical carcinogen, DMBA is a PAH that has been applied to the rat mammary tumour model20. It is perhaps the most studied PAH available, besides BaP. Data revealed that in vivo CYP1B1, and not CYP1A1, is the predominant enzyme in the metabolic activation of DMBA to carcinogenic metabolites15. Even though 3,4 diol-DMBA, 7-OHM-12DMBA and 1,2-epoxide3,4-diol-DMBA have all been proven to exhibit genotoxic effects, the latter is considered the ultimate carcinogen21. The benzylic carbon of 1,2-epoxide-3,4-diol-DMBA has been shown to induce substantial amounts of deoxyadenosine and deoxyguanosine adducts22. Minor adducts with the amino group of deoxycytidine and the 7-position of deoxyguanosine have been evidenced in some cases23,24. Some researchers claim that DMBA is a more potent carcinogen than BaP, as the latter tends to bind mostly to guanine residues on DNA, which results in a lesser potential for tumour initiation than hydrocarbondeoxyguanosine adducts25. Under the activation of CYP1B1, metabolites from DMBA have been shown to play a critical role in several tumours, where elevated levels of CYP1B1 were found relative to normal surrounding tissues. These cancers include brain, breast, colon lung and ovary11. In addition to its activity towards exogenous compounds, CYP1B1 also plays an important role in the metabolism of endogenous substrates such as oestrogen into reactive metabolites, namely, 4-hydroxyestradiol (Figure 3). Oestrogen is postulated to play a dual role in the carcinogenesis of breast and endometrial tissues by acting both as a proliferator and an initiator10. This then makes pre-menopausal women

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Critical review Table 1 A summary table of IC50 and Ki values (μM) obtained from the interaction of natural and synthetic compounds with CYP1B1 enzyme Natural/synthetic compounds

Inhibition of CYP1B1 (μM) IC50

Reference

Ki

Chromene amides CA1 CA2 CA3 CA4

15.36 37.04 179.30 18.14

30

1.42 0.14

31

Prenylated bromo hydroquinones 7-hydroxycymopochromanone 7-hydrocycymopolone Flavones Chrysin Apigenin Luteolin Biacelein Scutellarein AcaceƟn DiosmeƟn Eupatorin Eupatorin-5-OMe Genkwanin Cirsiliol Kaempherol QuerceƟn MyriceƟn Crysoeriol

0.024 0.3, 0.025 0.079

0.012 0.029

0.48 0.02 1.1 19.7

0.016 0.064 0.056 0.26 0.22 0.007 0.016 0.035 0.67 > 2.34 > 0.8 0.043, 0.10 0.023 0.027, 0.23

37–39

Flavanones Eriodictyol Homoeriodictyol Naringenin HespereƟn Pinocembrin IsosakuraneƟn

39,40

1.28 0.24. 1.76 3.66 0.51 1.68 1.02

Flavonole QuerceƟn Quercetrin Amentoflavone IsoquerceƟn Kaempferol RuƟn Naringenin

0.55 4.7 4.6 1.4 0.48 27 21

0.12 1.0 0.99 0.89 0.10 6.0

37,38

0.8 0.90 2.60 0.91

41

0.7 0.5

43

SƟlbene Trans resveratrol PinosƟlbene DesoxyrhaponƟgenin PterosƟlbene

42

Anthraquinone pigments Purpurin Alizarin




drug resistance as shown by research conducted by Rochat et al.26. They investigated the effect of 11 widely used chemotherapeutic drugs, of which 5 (5- luorouracil, vincristine, vinblastine, etoposide and cyclophosphamide) had no apparent effect on the enzyme, 3 (doxorubicin, daunomycin and tamoxifen) showed mixed or non-competitive inhibition and 4 ( lutamide, mitoxantrone, paclitaxel and docetaxel) exhibited competitive inhibition, indicating that the latter set may possibly be substrates of enzyme. More de initive research connecting the role of CYP1B1 in drug resistance was irst shown by McFadyen et al.27, when they coincubated the anti-cancer drug, docetaxel, with hamster ibroblast cells expressing CYP1B1. They noticed reduced cytotoxicity of the drug towards the cells when compared to those co-incubated with an inhibitor of the CYP1B1 enzyme. In addition to its involvement in carcinogenesis and drug resistance, CYP1B1 has also been shown to play a role in angiotensin-induced hypertension, which is linked to increased thirst, renal dysfunction as well as injury and in lammation28. Since there is concrete evidence linking the activity of CYP1B1 to the activation of noxious and copious carcinogens, it has been an accepted paradigm that inhibitors of the enzyme will prove useful as chemoprotectants from the activation of both endogenous and exogenous compounds. More recent research is also showing that inhibitors of this enzyme could be useful in not only preventing CYP1B1-induced resistance but also in preventing angiotensin-induced hypertension and, subsequently, renal failure28. As such, years of research has produced a library of plant extracts and isolated phytochemicals that can protect mammalian cells from the harmful effects of pro-carcinogens via their potent inhibition of the CYP1B1 enzyme. Some of these

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Critical review DMU-117 has shown promise in the treatment and prevention of gastrointestinal tumours in ApcMin+ mouse models without signs of toxicity. Though not as speci ic as DMU-135, phortress is a benzothiazole prodrug entered into phase 1 clinical trials and targets the aryl hydrocarbon receptor (AhR) in an antagonistic manner resulting in increased levels of CYPs 1A1 and 1B1. Once in the cells, phortress is hydrolysed into a lyophilic compound, SF203, which is then metabolized into electrophilic species under the activation of either CYPs 1A1 or 1B1. This subsequently results in DNA damage leading to cell death. Amino lavone, also undergoing phase 1 clinical trial, exhibits a similar mechanism of reducing cancer cell viability to that of DMU-135, but recent research has shown that its mechanism of action maybe reliant on the expression of sulfotransferase A1, which means a more detailed understanding of its mode of action is necessary. Additional research has also shown that chemopreventive agent, resveratrol, is metabolized into an anti-cancer agent, piceatannol, by CYP1B136. This indicates that the consumption of natural dietary agents not only provides protection against tumour initiation but treatment as well via the activity of CYP1B1.

Conclusion The activity of CYP1B1 has been implicated in the process of carcinogenesis, drug resistance and hypertension. As such for decades, inhibitors of this enzyme have been deemed possible chemoprotectants and, more recently, a solution to angiotensin-induced hypertension. On the other hand, recent research is now inding ways to exploit the elevated levels of activity of CYP1B1 in cancer tissues as a novel mechanism to exhibit tumourspeci ic cancer treatment, a mechanism sought after for decades. Also, it has been shown that dietary foods such as grapes containing lavonoids,

speci ically resveratrol, may also be able to exhibit cancer treatment properties due to the activity of CYP1B1. It then seems that more research is necessary to determine whether the carcinogenic properties of CYP1B1 will outweigh its possible chemotherapeutic applications and, if so, can a dual solution be found to not just utilize the elevated activities of CYP1B1 in cancer treatment but also in minimizing the process of carcinogenesis?

Acknowledgements We are grateful to the Forestry Conservation Fund (FCF), Jamaica; International Foundation for Science (IFS), Sweden; the University of the West Indies postgraduate fund; and the Luther Speare Scholarship for inancial support.

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products have even been shown to attenuate the aryl hydrocarbon signal transduction pathway, which is responsible for the transcription and upregulation of the CYP1 family29. Research conducted in our lab showed that chromene amides from the terrestrial plant, Amyris plumieri30 and prenylated bromoquinols, 7-Hydroxycymopochromanone and 7-hydroxycymopolone from the marine plant Cymopolia barbata31 inhibited the activity of CYP1B1. Other researched natural and synthetic compounds found to inhibit the activity of CYP1B1 and their potencies can be seen in Table 1. Despite its involvement in the process of carcinogenesis, drug resistance and renal hypertension, there is the notion that elevated levels of CYP1B1 in cancerous tissues relative to normal neighbouring ones could be exploited to provide a novel mechanism of addressing cancer treatment32. For decades science has sought to source treatment options that are more speci ic in targeting cancer cells than the ones we now have. Chemotherapeutic drugs now do not differentiate between rapidly dividing cancer cells and rapidly diving normal ones. As such, normal cells are attacked by the drugs and these include cells in the stomach lining, keratinocytes and bone marrow, resulting in vomiting, nausea, hair loss and a weak immune system among many other side-effects. Utilizing pro-drugs reliant on CYP1B1 activation could possibly solve these insufferable side-effects. As such several pro-drugs have been developed, of which a few have entered clinical trials6. These include 3,4Methylenedioxy-3’,4’,5’-trimethoxy chalcone (DMU-135)33, phortress34 and 5-amino-2,3- luorophenyl-6,8di luro-7-methyl-4h- benzopyran4-one (amino lavone)35. DMU-135 is metabolized within tumours only by CYP1B1 to its active metabolite, DMU-117. Being a potent nonselective tyrosine kinase inhibitor,

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