Herbal constituent’s and drug interactions involving cytochrome p450

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Pharmacovigilance: Effects of herbal components
on human drugs interactions involving
Cytochrome P450
Akansha Saxena, Kumar Parijat Tripathi, Sudeep Roy, Feroz Khan, Ashok Sharma
Bioinformatics and In Silico Biology Division, Central Institute of Medicinal and Aromatic Plants (Council of Scientific and Industrial Research), Lucknow 226015 (UP), India; Feroz Khan* - Email: f.khan@cimap.res.in; Phone: 91 522 2357133; Fax: 91 522 2342666; * Corresponding received November 9, 2008; accepted December 1, 2008; published December 31, 2008 Abstract:
Cytochrome P450 (CYP P450) enzymes are a superfamily of mono-oxygenases that are found in all kingdoms of life. The CYP
P450 enzymes constitute a large superfamily of haem-thiolate proteins involved in the metabolism of a wide variety of both
exogenous and endogenous compounds. The CYP activities have been shown to be involved in numerous interactions especially
between drugs and herbal constituents. The majority of serious cases of drug interactions are as a result of the interference of the
metabolic clearance of one drug by yet another co-administered drug, food or natural product. Gaining mechanistic knowledge
towards such interactions has been accepted as an approach to avoid adverse reactions. The inductions and inhibition of CYP
enzymes by natural products in the presence of a prescribed drug has led to adverse effects. Herbal medicines such as St. John’s
wort (Hypericum perforatum), garlic (Allium sativa), piperine (from Piper sp.), ginseng (Ginseng sp.), gingko (Gingko biloba),
soya beans (Glycine max), alfalfa (Medicago sativa) and grape fruit juice show clinical interactions when co-administered with
medicines. This review documents the involvement of CYP enzymes in the metabolism of known available drugs and herbal
products. We also document the interactions between herbal constituents & CYP enzymes showing potential drug-herb
interactions. Data on CYP450 enzymes in activation (i.e. induction or inhibition) with natural constituents is also reviewed.
Keywords: Cytochrome P450; CYP; Herb-drug interactions; inhibition; induction; natural products; natural ingredients;
phytomolecules

Background:
The name Cytochrome P450 derives from the fact that these
with a plethora of drugs available in the market, have been proteins have a haem group, and an unusual absorption associated with a majority of the metabolism-related drug- spectrum range. The reason for cytochrome P450 to absorb in drug interactions known to date [2, 3]. It is not surprising that
this range is due to the unusual ligand haem iron. Four much of the CYP in human is found in the liver, the main ligands are provided by nitrogen on the haem ring. The CYP organ for drug and toxin removal. However, a significant enzymes are a superfamily of haem containing enzymes. In amount is also found in the small intestine. There are over a humans, CYP enzymes are important in the production of thousand different types of CYP known till date. compounds such as cholesterol, corticosteroids and fatty Nevertheless, the number of CYP types in human is relatively acids. The most important feature of the CYP enzymes is its unique ability to activate molecular oxygen and to subsequently insert a single oxygen atom stereo-specifically The P450 proteins are categorized into families and into inert chemical bonds. CYP enzymes catalyses the subfamilies using sequence similarity. Sequences that are insertion of oxygen into activated carbon – hydrogen bonds greater than 40% identity are considered within a family. to yield alcohol (e.g. RH + O2 + 2H+ + 2e– → ROH + H2O). Sequences that are greater than 55% identity are considered However, they can also carry out plethora of other reactions within a super-family. Humans have 57 CYP genes and more including epoxidation, dealkylation and heteroatom oxidation [1]. The majority of serious cases of drug interactions are as a
P450 genes and 43 subfamilies. The summary of the genes result of the interference of the metabolic clearance of one and proteins encoded is given in Table 1 (supplementary
drug by yet another co-administered drug, food or natural material). Several of them have been identified as particularly product. Gaining mechanistic knowledge towards such important in oxidative metabolism. They far interactions has been accepted as an approach, for avoiding adverse reactions. The CYP P450 enzymes, which interact ISSN 0973-2063 (online) 0973-8894 (print) Bioinformation 3(5): 198-204 (2008) 2008 Biomedical Informatics Publishing Group Bioinformation by Biomedical Informatics Publishing Group open access
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Enzyme induction occurs for CYP with appropriate
reduce its expected therapeutic capacity due to depletion of substrates. The activity of CYP oxidases do vary across its plasma concentration. A higher dose of the parent drug is population due to polymorphism. Such differences in activity therefore required for effective therapy, with further dosage have clinical consequences, especially when multiple drugs tailoring as and when the inducer effects are withdrawn. This is true in many instances. It should be note that CYP enzyme induction rarely leads to toxicity, except in cases where the Biological description of cytochrome P450
metabolite is particularly harmful. For example, CYP1A1 The CYP enzymes involved in drug metabolism in humans and 1A2 have been implicated in increased carcinogenic are expressed predominantly in the liver. However, it is also activation of chemicals. Thus they are considered as a present in large and small intestines, lungs and brain. They potential risk factor in certain cancers and hence drugs that are insoluble proteins bound to the endoplasmic reticulum, induce these reactions are preferentially avoided by the with complex mechanistic and structural features. However, pharmaceutical industry [10, 12]. Several popular herbs have
the first crystal structures of mammalian CYP enzymes have been reported to participate in interactions with medicinal recently been determined, namely CYP2C5, CYP2B4, drugs leading to clinically relevant drug adversities. A few CYP2C9 and CYP3A4 [4, 5] and thus, much progress can be
examples that involve CYP enzymes and are highlighted in expected in this area in near future. It is believed that 15-20 this review along with predicted as well as experimental different CYP enzyme isoforms contribute to drug interactions are summarized in Table 2 (supplementary
metabolism in the human liver. However, the CYP enzymes material). A few examples of herbal constituents and drugs 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 are considered most that interact with human CYP enzymes are highlighted in important among them [1, 2, 6]. These have different yet
Table 3 (see supplementary material).
complementary substrate specificities with ability to metabolize a vast array of xenobiotics. CYP3A4 acts on most Hypeforin from St. John’s Wort herb (Hypericum
lipophilic substrates and is known to metabolize >50% of the perforatum)
drugs in the liver [7], whilst CYP2D6 exhibits a preference
A popular herb largely used in the treatment of depression is for positively charged molecules, usually with a basic St. John's Wort (SJW). It has been implicated with a number nitrogen. CYP2C9 metabolizes weakly anionic molecules, of clinically significant interactions with medicinal drugs, CYP1A2 uses poly-aromatic hydrocarbons and CYP2E1 uses one of the more potentially fatal being with cyclosporine. small and soluble organics. Therefore, the CYP system can Cyclosporine is an immunosuppressant with a narrow metabolize almost any organic xenobiotic [7, 8]. Most drugs
therapeutic index administered to transplant patients. In are cleared by CYP proteins. Drugs can increase or decrease reported cases, consumption of various levels of SJW (from the activity of one or more CYP enzymes, which alters the 300 mg/day for 4 weeks to 2 or 3 × 300 mg/day for 6 rate at which the drug is degraded and cleared from the body. months) lead to a decrease in cyclosporine levels below the This can work both ways. When a drug increases the activity desirable effective therapeutic range of 200-350 μg/L causing of a CYP protein, CYP can render the drug ineffective, cellular rejection of the tissue [13]. The induction of
because it is cleared too quickly from the body. CYP3A4 through the activation of pregnane X-receptor by Alternatively, when a drug inhibits a CYP protein, CYP may both the crude extract and hyperforin (one of the active not prevent the drug from accumulating to toxic levels, even ingredients) has been demonstrated in primary human to the extent of causing an overdose. CYP1, CYP2, CYP3 hepatocyte cultures. In addition, the induction of intestinal and CYP4 are the most important for drug biotransformation multidrug resistant transporter protein MDR1/P-glycoprotein among CYP proteins and CYP3A4 is the most prevalent CYP has been demonstrated in clinical and preclinical (rat in vivo) in the body and is known metabolise several drugs [9, 10,
investigations [14, 15]. Results of these studies explain the
combined increase in absorption and metabolism of drugs such as cyclosporine in the presence of SJW, thus resulting in Metabolism based interactions
a severe decrease in the serum availability of the drug leading The most common form of drug interactions entail a foreign to declined therapy. They also provide a mechanism-based chemical acting either as an inhibitor or an inducer of the explanation for other SJW-mediated adversities in the CYP enzyme isoform responsible for metabolizing an presence of prescription medicines whose metabolism is administered medicinal drug, subsequently leading to an catalyzed by CYP3A4. Such instances include the loss of unusually slow or fast clearance of the drug. More rarely, anticoagulant activity of warfarin and the intermenstrual enzyme stimulation can occur where direct addition of one bleeding in several females on the contraceptive, compound enhances the rate of reaction for substrate [3].
ethinylestradiol [16, 17]. A recent clinical study examining
Inhibition of drug metabolism will result in an elevation of its the metabolism of omeprazole has established that in addition concentration in tissues. This leads to various adverse to the induction of CYP3A4, SJW enormously decreases the reactions, particularly for drugs with a low therapeutic index. plasma concentration of the drug through the induction of Constant research in this field has been successfully kept CYP2C19, which is responsible for the hydroxylation of the updated by developing web based databases for reported and drug [18].
likely drug candidate interactions. The induction of a CYP enzyme isoform responsible for the metabolism of a drug can ISSN 0973-2063 (online) 0973-8894 (print) Bioinformation 3(5): 198-204 (2008) 2008 Biomedical Informatics Publishing Group Bioinformation by Biomedical Informatics Publishing Group open access
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Allicin from Garlic (Allium sativum)
Pharmacovigilance
Garlic is used for the reduction of hypertension and The under-reporting of adverse drug reactions in developing hyperlipidaemia. It has been implicated in the decrease of the countries including India, Sri Lanka and the Philippines [31],
plasma concentration of protease inhibitor saquinavir [19,
is possibly the main reason why only 3% of the adverse drug 20]. The induction of gut CYP3A4 by garlic was thought to
reactions reported in the WHO database have been added be a plausible explanation for the reduction in bioavailability from the developing countries where approximately 80% of of the drug known to be primarily metabolized by CYP3A4 the world's population lives. In these countries, a strong [21]. The active ingredient allicin has also shown potent
practice of traditional medicine exists and adverse drug inhibitory activity on CYP2C9 and 2C19. The potential drug reactions go unrecognized as part of the healing process. adversities predicted for each of these active ingredients as a There is generally a misconception that natural therapies are result of their interactions with CYP enzymes has to be safe. The reluctance of physicians trained in Western examined in a clinical setting to know the extent to which medicine to give recognition to these traditional practices garlic can interact with co-medications [20, 22].
also leads to a lack of acknowledgement of possible drug- herb interactions [32]. The world consumption of natural
Piperine from Piper (Piper nigrum)
products for medicinal purposes is immense. According to In clinical trials, piperine has shown to increase the WHO estimates, 30-50% of total medicinal consumption in bioavailability of phenytoin, propranolol and theophylline China can be accounted by herbal preparations, 70% of []. Although in vivo study on rat has demonstrated that
Canadians and >50% of Europeans, North Americans and piperine treatment suppressed CYP2E1 expression and persons living in other industrialized regions have used enhanced 2B and 1A expression [12, 24]. It should be noted
complementary medicine at least once, in addition to the high that the clinical observations are due for CYP isoforms for incidence of practice in Africa, Latin America and Asia [8,
Ginsenoside from Ginseng (Panax ginseng)
Future prospects:
Ginseng (Panax ginseng) has been shown to induce mania The role of metabolism in drug-herb components interactions when used concomitantly with phenelzine []. Bipolar
and in turn the role of CYP enzymes in such interactions disorder (mania) also known as manic depression (or bipolar cannot be overstated. Studies that could establish the various depression) and is a common mood disorder that affects phenotypes and genotypes of CYP alleles for populations in various ethnic groups, the impact of environmental, dietary (www.medicinenet.com/bipolar_disorder/article.htm). and social habits on CYP activity, the metabolism of natural vitro studies using both crude ginseng extract and total products by CYP enzymes and the impact of these natural saponins at high concentrations (>2000 μg/mL) showed the products on the CYP enzyme activities would allow initial inhibition of CYP2E1 activity in mouse and human predictions. Hence, prevention of likely adverse drug microsomes [26]. Ginsenoside caused weak inhibitory
reactions involving these crucial enzymes is possible. activity against CYP3A4, CYP2D6, CYP2C19 and CYP2C9 Gaining a mechanism based understanding lies at the root of while ginsenoide increased the activity of CYP2C9 and avoiding these enzyme-related drug adversities. Cytochrome CYP3A4 [26, 27]. The effect of this herb and its ingredients
P450 is an ideal target for these studies. The ability to make on CYP enzymes is yet to be substantiated in an in vivo such predictions would be of enormous benefit to pharmacogenomics studies as P450 plays a vital role in the metabolism of drugs. The Cytochrome is of special interest in Ginkgolic acid from Gingko (Gingko biloba)
pharmacology as it is responsible for the metabolism of many In vitro and in vivo analysis carried out on hepatic and pharmacologically active molecules. The use of in silico intestinal CYP enzymes of rat, have demonstrated that the protein–drug interactions studies and computer aided drug leaf extract inhibits the metabolism of diltiazem, which is a designing approach and quantum mechanical calculations typical substrate for CYP3A [28] and also induces CYP2B
will allowing to know the mechanism of interaction of P450 enzymes . In addition, ginkgolic acids were shown to be with herbal constituents. This in turn will allow theories potent inhibitors of CYP1A2, CYP2C9 and CYP2C19 under regarding unknown features of human P450 to be tested and CYP enzymes case study [30]. Although flavanol aglycones
predictions to be made for the result of an interaction of showed significant inhibitory activity against CYP1A2, 2C9 herbal constituents within a given P450. The computational and 3A, recent findings showed that the most abundant approaches could be used to analyze the interactions, components of gingko preparations in clinical use (terpene regarding the processes on such binding which helps to trilactones and flavanol glycosides) do not significantly predict new conformations of active site. The introduction of inhibit major CYP enzymes in microsomes of human’s liver some of the determined contact residues of the active site into [16, 22, 29]. The variations of constituents of gingko
the model will allow the orientation of herbal constituents (ginkgolides, biobalides, and flavone glycosides) and their bioavailabilities could explain the disparity in findings, in addition to species variability in drug metabolism. ISSN 0973-2063 (online) 0973-8894 (print) Bioinformation 3(5): 198-204 (2008) 2008 Biomedical Informatics Publishing Group Bioinformation by Biomedical Informatics Publishing Group open access
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Acknowledgment:
U. A. Meyer and U. M. Zanger, Annu Rev Pharmacol We acknowledge the Council of Scientific and Industrial Research (CSIR), New Delhi and Department of A. D. Rodrigues and S. Wong, London: Scientific and Biotechnology (DBT), New Delhi for financial supports to Regulatory Perspectives, 65: 101 (1997) the Central Institute of Medicinal and Aromatic Plants Q. Yue et al., Lancet, 355: 576 (2000) L. Wang et al., Clin Pharmacol Ther.,75: 191 (2004) D. Guyonnet et al., Mutat Res., 466: 17 (2000) References:
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Citation: Saxena et al., Bioinformation 3(5): 198-204 (2008)
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Supplementary material

Function Category
Drug and steroid (especially estrogen) metabolism Drug and steroid (including testosterone) metabolism Arachidonic acid or fatty acid metabolism Bile acid biosynthesis 7-alpha hydroxylase of steroid nucleus 2 subfamilies, CYP17 Steroid biosynthesis, 17-alpha hydroxylase CYP19 Steroid biosynthesis: aromatase synthesizes estrogen ISSN 0973-2063 (online) 0973-8894 (print) Bioinformation 3(5): 198-204 (2008) 2008 Biomedical Informatics Publishing Group Bioinformation by Biomedical Informatics Publishing Group open access
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CYP27 Varied
CYP27B1 (vitamin D3 1-alpha hydroxylase, activates vitamin D3) CYP27C1 (unknown function) CYP39 7-alpha hydroxylation of 24-hydroxycholesterol Table 1: Classification of the CYP family on the basis of CYP isoform and function is given.
Name of medicinal
Herbal component
IUPAC name
and Chemical
4-Hydroxy-5-isobutyryl-6-methyl-1,3,7-tris-(3- methyl-but-2-enyl)-6-(4-methyl-pent-3-enyl)- 3-prop-2-enylsulfinylsulfanylprop-1-ene 65036 (2E,4E)-5-(1,3-benzodioxol-5-yl)-1-piperidin-1- (3S,5R,8R,9R,10R,14R,17S)-17-(2-hydroxy-6- methylhept-5-en-2-yl)-4,4,8,10,14-pentamethyl-2,3,5,6,7,9,11,12,13,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol 2-hydroxy-6-[(Z)-pentadec-8-enyl]benzoic acid Table 2: Medicinal plants with their herbal components, IUPAC name, Chemical structure and PubChem CID number. (Note: *
= PubChem compound identity descriptor number (http://pubchem.ncbi.nlm.nih.gov/)).
Medicinal
Drug Experimental CYP
Symptom of
Mechanism
constituent
interaction
involved
chemical
(isoform)
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Table 3: Assessment of herbal components on drug interactions and effects on CYP activities
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