The relevance of studying Cytochrome P450s CYPs in the natural product industry

CYPs are involved in the metabolism of almost all drugs in the market today and have been shown to be crucial in the metabolism of a variety of natural products. They are linked to numerous drug-drug interactions [ 12] ; of particular interest has been the issue of drug-natural product interactions which has received much attention both in the scientific and non-scientific communities, given the global trend of increasing consumption of natural products. Table 1 illustrates a few examples, the involvement of specific CYPs, their toxicological and pharmacological impact and the mechanisms responsible for such interactions.

Table 1. Examples of a few reported natural product-drug interactions involving CYPs

Agent

Drug

Enzyme

Mechanims

Observed or expected impact

Cyclosporin,

Warfarin

CYP3A4

Induction

Decreased plasma levels of the drugs leading inadequate therapeutic effects at the given concentration.

Grapefruit juice, Liquorice Root, Milk thistle

Cyclosporin,

Simvastin,

Sauinavir,

Buspirone,

Felodipine, and atleast 20

other drugs

CYP3A4, CYP1A2

Inhibition

Increased plasma concentration of the prescribed drug leading to various toxicities.

Cruciferous vegetables, chargrilled meats, Chinese medicine Wu-chu-yu-tang

Warfarin,

Theophylline,

Clozapine

CYPIA2

Induction

The efficacy of the drugs is reduced and would require higher drug concentrations. In addition, CYPlA2's involvement in activating procarcinogens may be enhanced.

Garlic, Watercress

Chlorzoxazone

CYP2E1

Inhibition

Increase in plasma levels of the drug leading to hepato toxicity.

The numerous reports of natural-product drug interactions [14,16-18] strongly suggest the value of undertaking such experiments involving the taking of natural products with prescription medicines, to correct the general assumption that natural medicines do not give rise to any adverse reactions alone or with co-medications.

Structure-activity relationship studies

Mammalian CYP enzymes are all membrane bound, which poses a huge problem in obtaining sufficient quantities of solubilized, purified recombinant enzymes for crystallization trials. The only mammalian crystal structure available currently is that of the rabbit CYP2C5 [19], which has provided a template for modeling the human enzymes [20]. Previously, in the absence of the rabbit model, the bacterial P450 models provided the template for generating ligand-bound active site models with concurrent data derived from Nuclear Magnetic Resonance (NMR) spectroscopy measurements serving as restraints [21,22]. There are on-going attempts to generate detailed structural models through various homology modeling [23], NMR measurements and biochemical means [24], This is useful in generating the best model for the enzyme. It is expected that these models would then serve as reliable means for predicting the interaction, and the outcome of the interaction, between the enzyme and the xenobiotic of interest.

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