Rupika Delgoda

Herbal interactions involving cytochrome p450 enzymes: a mini review.

The metabolism of a drug can be altered by another drug or foreign chemical, and such interactions can often be clinically significant. Cytochrome P450 (CYP) enzymes, a superfamily of enzymes found mainly in the liver, are involved in the metabolism of a plethora of xenobiotics and have been shown to be involved in numerous interactions between drugs and food, herbs and other drugs. The observed induction and inhibition of CYP enzymes by natural products in the presence of a prescribed drug has (among other reasons) led to the general acceptance that natural therapies can have adverse effects, contrary to the popular beliefs in countries where there is an active practice of ethnomedicine. Herbal medicines such as St. John’s wort, garlic, piperine, ginseng, and gingko, which are freely available over the counter, have given rise to serious clinical interactions when co-administered with prescription medicines. Such adversities have spurred various pre-clinical and in vitro investigations on a series of other herbal remedies, with their clinical relevance remaining to be established. Although the presence of numerous active ingredients in herbal medicines, foods and dietary supplements complicate experimentation, the observable interactions with CYP enzymes warrant systematic studies, so that metabolism-based interactions can be predicted and avoided more readily. This article highlights the involvement of CYP enzymes in metabolism-related drug-herb interactions and the importance of gaining a mechanism-based understanding to avoid potential adverse drug reactions, in addition to outlining other contributory factors, such as pharmacogenetics and recreational habits that may compound this important health issue.

The prevalence of herbal medicine home use and concomitant use with pharmaceutical medicines in Jamaica

ETHNOPHARMACOLOGICAL RELEVANCE The work described in this paper aimed to study the prevalence of herbal medicine use in treating illness and concomitant use with pharmaceutical medicines in Jamaica. MATERIALS AND METHODS A survey using a structured questionnaire was administered by a trained interviewer to randomly selected adults in systematically selected households within randomly selected urban and rural clusters. Categorical data analysis was performed using Stata version 10 software. RESULTS 91.4%(372/407) of selected people agreed to participate. 72.6%(270/372) self-medicated with herbs within the previous year. Commonly treated were illnesses of the respiratory system (RS, 77.8%(210/270)), gastro-intestinal tract (GIT, 53.3%(144/270)) and health maintenance using tonics (29.6%(80/270)). 26.7%(72/270) of respondents used pharmaceuticals concomitantly with medicinal plants. Commonly treated were illnesses of the RS (20.4%(55/270)), GIT (13.7%(37/270)) and hypertension (10.0%(27/270)). 19.4% (14/72) of physicians knew of such practices. There was significant association of herb use with/without drugs with age (p<0.001), employment status (p<0.001), religion (p=0.004), gender (p=0.02) and educational level (p=0.031). Thus prevalence of herb use alone was greatest amongst people aged 35-44 and 45-54 years; those employed; Rastafarians; those without health insurance; males and people who had completed secondary education. Whilst prevalence of concomitant herb-drug use was greater amongst people aged 65 years and older; those retired; those of religions other than Rastafarians and Christians, females and people who had attained primary education and below. CONCLUSIONS Self-medication with herbs in Jamaica is highly prevalent and highest for self-limiting conditions of the RS, GIT and health maintenance with tonics. Concomitant herb and drug use is highest for self-limiting conditions of the RS, GIT and hypertension, and the use of combined therapy highlights the need for investigations on potential drug-herb interactions. Physicians have limited awareness and knowledge of such concomitant usage, further highlighting the need for increased dialogue with patients, knowledge of medicinal plants and their uses and a heightened pharmacovigilance to avoid adversities that may arise from potential drug-herb interactions.

The prevalence of herbs use in conjunction with conventional medicines in Jamaica.

UNLABELLED Due to the global rise in the popularity of herbal medicines, adversities resulting from concomitant use of both prescription drugs and herbs are becoming an increasingly important public health issue. OBJECTIVES To estimate the prevalence of the use of herbal medicines among persons on prescription medicines in Jamaica. Findings are thought to aid in estimates of the risk of adversities from drug-herb interactions through laboratory investigations and to provide awareness among policy makers responsible for the design of appropriate pharmacovigilance systems in the country. METHODS A survey was conducted in eighteen pharmacies throughout Jamaica and patients or parents/carers of children who were on at least one prescription medicine were administered a structured questionnaire by trained interviewers. RESULTS Of 399 persons invited to participate in the study 365 (91.5% response rate) agreed to do so and were included in the study. This study population consisted of 306 adults and 60 children and of that 243 adults (80.6%) and 45 children (75.6%) engaged in the concomitant use of herbs and drugs. Patients with a variety of disease conditions, in both rural and urban environs engaged in concomitant herb-drug use. Persons with higher salary (P<0.1) and those with health insurance (P<0.02) tended to have a lower prevalence of herb-drug concomitant use. Among persons indicating such practices the most commonly cited reason for concurrent use of prescription medicine and herbal preparations was the belief that there was no harm in taking both (269, 94.0%) followed by the belief that the prescription medicine alone was not adequate cure (211, 71%). Only 55 (18%) respondents who practised such co-medication indicated that their doctors knew of their use of herbal preparations. CONCLUSION There is a high prevalence of herb-drug concomitant use in Jamaica, and an awareness within the medical community and those monitoring adversities would serve well to mitigate risks from potential drug-herb interactions.

Role of the modulation of CYP1A1 expression and activity in chemoprevention.

As one of the main extra‐hepatic cytochrome P450 (CYP) enzymes, CYP1A1 has been comprehensively 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 benzo‐a‐pyrene (BaP), a copious and noxious compound present in coal tar, automobile exhaust fumes, cigarette smoke and charbroiled food, is metabolised by CYP1A1 and has been studied in great detail. Other compounds reliant on the same enzyme for their activation include 7,12 dimethylbenz(a)anthracene (DMBA) and heterocyclic amine, 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP). This review takes an in‐depth look at a number of phytochemicals, plant extracts and a few synthetic compounds that have been researched and deemed potential chemopreventives via their interaction with the activity and expression of CYP1A1. It will also review a useful active site model of CYP1A1. Based on inhibitors of CYP1A1 that have demonstrated in vivo use as chemopreventors, CYP1A1 is a useful initial target for screening compounds with such potential, with the use of rapid in vitro and/or in silico assessments. Chemoprevention is a means by which healthy tissues are protected via the prevention, inhibition or reversal of carcinogenesis. This review focuses on one important pathway of carcinogenesis and identifies the important role that CYP1A1 plays in that pathway. It is hoped that highlighting the importance of such a key target, will help revive further research into and application of inhibitors of CYP1A1 towards generating improved chemopreventors. Copyright

Cytochrome P450 1 enzyme inhibition and anticancer potential of chromene amides from Amyris plumieri.

Cytochrome P450 (CYP) enzyme inhibitory properties of six chromenylated amide compounds (CAs) from Amyris plumieri are described. Inhibition of CYP microsomes (CYP1A1, CYP1A2, CYP1B1, CYP2D6, CYP3A4 and CYP2C19) was monitored using a fluorescent assay. Potent inhibition was found against CYP1A1 with IC(50) and K(i) for CA1 (acetamide), being the lowest at 1.547 ± 1.0 μM and 0.37 μM respectively, displaying non-competitive kinetics. The selectivity for CYP1A1 was increased in CA3 (butanamide), which also exhibited cytotoxicity against breast cancer cells, MCF7 with an IC(50) of 47.46 ± 1.62 μM. Structure-activity relationship studies provide insight at a molecular level for CAs with implications in chemoprevention and chemotherapy.

Possible mechanisms of action of the aqueous extract of Artocarpus altilis (breadfruit) leaves in producing hypotension in normotensive Sprague-Dawley rats.

Context and objectives: Artocarpus altilis (Parkinson) Fosberg (Moraceae) (breadfruit) leaves are used as an antihypertensive remedy. We investigated the possible mechanisms of action of its aqueous extract and its effect on cytochromes P450 (CYP) enzyme activities. Materials and methods: Intravenous administration of an aqueous leaf extract (20.88–146.18 mg/kg) of A. altilis on mean arterial pressure and heart rate were recorded via cannulation of the carotid artery on anaesthetized normotensive Sprague–Dawley rats. Recordings of the contractile activity of the aortic rings to the extract (0.71–4.26 mg/mL) were studied using standard organ bath techniques. Inhibitions of human CYP3A4 and CYP2D6 enzyme activities were evaluated by means of a fluorometric assay in 96 well plates using heterologously expressed microsomes. Results: A. altilis caused significant (p < 0.05) hypotensive and bradycardiac responses unaffected by atropine (2 mg/kg) and mepyramine (5 mg/kg), but attenuated by propranolol (1 mg/kg) and N(G)-nitro-l-arginine methyl ester (5 mg/kg). The extract (0.71–4.26 mg/mL) significantly (p < 0.05) relaxed phenylephrine (10−9–10−4 M) and 80 mM KCl-induced contractions in endothelium intact and denuded aortic rings; and caused a significant (p < 0.05) rightward shift of the Ca2+ dose-response curves in Ca2+-free Kreb’s solution. Moderate inhibitions of cytochrome P450s (CYP3A4 and CYP2D6) enzyme activities with IC50 values of 0.695 ± 0.187 and 0.512 ± 0.131 mg/mL, respectively, were produced. Conclusion: A. altilis exhibits negative chronotropic and hypotensive effects through α-adrenoceptor and Ca2+ channel antagonism. Drug adversity effects are unlikely if the aqueous leaf extract is consumed with other medications reliant on CYP3A4 and CYP2D6 metabolism. This study thus provides scientific evidence for the use of the breadfruit in the treatment of hypertension.

Inhibition of CYP1A1 by quassinoids found in Picrasma excelsa.

Infusions of the plant Picrasma excelsa, known as Jamaican bitterwood tea, are commonly consumed to lower blood sugar levels in diabetics who are already on prescription medicines. We therefore investigated the inhibition properties of this tea against a panel of cytochrome P450 (CYP) enzymes, which are primarily responsible for the metabolism of a majority of drugs on the market. The two major ingredients, quassin and neoquassin, were then isolated and used for further characterization. Inhibition of the activities of heterologously expressed CYP microsomes (CYPs 2D6, 3A4, 1A1, 1A2, 2C9, and 2C19) was monitored, and the most potent inhibition was found to be against CYP1A1, with IC (50) values of 9.2 microM and 11.9 microM for quassin and neoquassin, respectively. The moderate inhibition against the CYP1A1 isoform by quassin and neoquassin displayed partial competitive inhibition kinetics, with inhibition constants ( K(i)) of 10.8 +/- 1.6 microM, for quassin and competitive inhibition kinetics, with a K(i) of 11.3 +/- 0.9 microM, for neoquassin. We then docked these two inhibitors into the active site of a model of CYP1A1, which provided insight at the atomic level into the structure-activity relationship of quassinoids with respect to this important CYP isoform known to be an activator of carcinogens, thus providing a useful basis for the search for more potent inhibitors of CYP1A1 that may have implications in chemoprotection.

Cytotoxic and potent CYP1 inhibitors from the marine algae Cymopolia barbata

Background Extracts from the marine algae Cymopolia barbata have previously shown promising pharmacological activity including antifungal, antitumor, antimicrobial, and antimutagenic properties. Even though extracts have demonstrated such bioactivity, isolated ingredients responsible for such bioactivity remain unspecified. In this study, we describe chemical characterization and evaluations of biological activity of prenylated bromohydroquinones (PBQ) isolated from the marine algae C. barbata for their cytotoxic and chemopreventive potential. Methods The impact of PBQs on the viability of cell lines (MCF-7, HT29, HepG, and CCD18 Co) was evaluated using the MTS assay. In addition, their inhibitory impact on the activities of heterologously expressed cytochrome P450 (CYP) enzymes (CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, and CYP3A4) was evaluated using a fluorescent assay. Results 7-Hydroxycymopochromanone (PBQ1) and 7-hydroxycymopolone (PBQ2) were isolated using liquid and column chromatography, identified using 1 H and 13 C NMR spectra and compared with the spectra of previously isolated PBQs. PBQ2 selectively impacted the viability of HT29, colon cancer cells with similar potency to the known chemotherapeutic drug, fluorouracil (IC50, 19.82 ± 0.46 μM compared to 23.50 ± 1.12 μM, respectively) with impact toward normal colon cells also being comparable (55.65 ± 3.28 compared to 55.51 ± 3.71 μM, respectively), while PBQ1 had no impact on these cells. Both PBQs had potent inhibition against the activities of CYP1A1 and CYP1B1, the latter which is known to be a universal marker for cancer and a target for drug discovery. Inhibitors of CYP1 enzymes by virtue of the prevention of activation of carcinogens such as benzo-a-pyrene have drawn attention as potential chemopreventors. PBQ2 potently inhibited the activity of CYP1B1 (IC50 0.14 ± 0.04 μM), while both PBQ1 and PBQ2 potently inhibited the activity of CYP1A1 (IC50s of 0.39 ± 0.05 μM and 0.93 ± 0.26 μM, respectively). Further characterizations showed partial noncompetitive enzyme kinetics for PBQ2 with CYP1B1 with a Ki of 4.7 × 10–3 ± 5.1 × 10–4 μM and uncompetitive kinetics with CYP1A1 (Ki = 0.84 ± 0.07 μM); while PBQ1 displayed partial non competitive enzyme kinetics with CYP1A1 (Ki of 3.07 ± 0.69 μM), noncompetitive kinetics with CYP1A2 (Ki = 9.16 ± 4.68 μM) and uncompetitive kinetics with CYP1B1 (Ki = 0.26 ± 0.03 μM) . Conclusions We report for the first time, two isolated ingredients from C. barbata, PBQ1 and PBQ2, that show potential as valuable chemotherapeutic compounds. A hydroxyl moiety resident in PBQ2 appears to be critical for selectivity and potency against the cancer colon cells, HT29, in comparison to the three other malignant cell lines studied. PBQs also show potency against the activities of CYP1 enzyme which may be a lead in chemoprevention. This study, the first on isolates from these marine algae, exemplifies the value of searching within nature for unique structural motifs that can display multiple biological activities.

Hyptis verticillata Jacq: A review of its traditional uses, phytochemistry, pharmacology and toxicology

ETHNOPHARMACOLOGICAL RELEVANCE Hyptis verticillata Jacq. (Lamiaceae) (John Charles) is an important medicinal plant with a long history of traditional use, originating in Central America and now extending from Florida to Colombia and across the Caribbean. Records of its earliest use date back to the ancient Mayan and Aztec cultures of Mesoamerica. There is no indication that this plant is being used outside of the Americas. AIM OF THE REVIEW This review aims to provide a comprehensive overview of the traditional use, phytochemistry, pharmacological activity and toxicology of Hyptis verticillata and to highlight the opportunities for greater development of the plants medicinal properties at a local and international level. MATERIALS AND METHODS An extensive and systematic review of the literature was undertaken and all relevant abstracts and full-text articles analysed and included in the review. KEY FINDINGS A wide range of traditional uses are cited in the literature, from internal uses for conditions affecting the respiratory system, digestive tract and gynaecological system to external uses for conditions affecting the skin and musculoskeletal system. Pharmacological studies to date have demonstrated significant activity which support the traditional use of the plant as an antiinflammatory, antimicrobial, antisecretory agent and hormone modulator. In addition studies have identified anti-cancer, acaricidal, insecticidal and molluscicidal activity. No clinical trials had been completed at the time of this review. A number of key phytochemicals have been isolated, identified and published to date including: 17 lignans; 4 triterpenes; 11 diterpenes, 3 sesquiterpenes, 3 monoterpenes, 2 flavonoids, 1 polyphenol and 1 alkaloid. Nine of these phytochemicals are novel to Hyptis verticillata. Plant extracts and isolated phytochemicals exhibit a broad range of activities that include: antimitotic; antiproliferative; cytotoxic; antioxidant; antiinflammatory; antibacterial; antifungal; antiviral; anti-HIV; antisecretory; hepatoprotective; insecticidal and acaricidal. CONCLUSIONS Hyptis verticillata is a medicinal plant with current widespread traditional use in the Americas that warrants further research, clinical trials and product development to fully exploit its medicinal value.

A patent review on the development of human cytochrome P450 inhibitors.

Introduction: CYP, a ubiquitous superfamily of enzymes expressed in major organs in humans, plays a key role in biosynthesis of steroids and metabolism of xenobiotics. Inhibitors of these vital enzymes provide, as tools, the opportunity to gain an insight to their role in a myriad of bioactivity and to intervene as therapeutics in disease. Areas covered: This article reviews granted patents for human CYP inhibitors from the US and European territories within the past decade. Expert opinion: Granted patents, albeit mostly embodying evidence from in vitro and limited preclinical trials, demonstrate good potential for use in industry and the clinic following future human trials. Indeed, only a handful is on the market or under clinical evaluation. Diagnostic monoclonal antibodies (mAbs) show high specificity for CYP families 1, 2, and 3, while potent inhibitors of CYPs 17, 19, 24, 26, 3A4 activities, in use with or without other drugs, display potential in treating prostate and breast cancers, dermatology, and improved retroviral therapy, although some may have challenges in delivery to target tissues. The involvement of this superfamily of enzymes in cellular functions, a multitude of disease states, and pharmacogenetics make them ideal candidates to better understand contemporary human health issues and identification of targeted, specific, and potent inhibitors is a useful strategy to employ, toward achieving that wider goal.