CYP metabolism And Regulation


Cytochrome P450 enzymes (CYPs) are present in most tissues of the body and are the major oxidation enzymes involved in the synthesis, metabolism and bioactivation of a number of molecules and chemicals and account for about 75% of the total number of metabolic reactions within the human body[1]. Human CYPs are primarily membrane-associated proteins located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells and 57 human genes encoding various CYP enzymes have been identified. In addition to playing a key role in the synthesis and breakdown of hormones, synthesis of cholesterol and metabolism of vitamin D, CYPs also metabolise xenobiotic substances including drugs, environmental chemicals and products of endogenous metabolism.

Phase I CYP oxidation via NADPH-CYP reductase is a critical step in the elimination of lipophilic xenobiotics, with excretion of highly polar products occurring following Phase II conjugation[2]. Although most CYP oxidations are detoxication pathways, the clearance of some substrates can result in the production of reactive cytotoxic metabolites, such as the activation of food-derived aromatic amines to DNA-binding sites[3]. The majority of CYP enzymes primarily act by altering gene transcription, though some also operate through post-transcription mechanisms[4]. Basal regulation of CYP expression occurs via the Jak-STAT signalling pathways following binding of growth factors (including growth hormone GH), cytokines and peptide hormones to relevant cell surface receptors[5]. Nutritional stresses including vitamin A deficiency [6], alcohol ingestion[7] and fasting[8] have been shown to dysregulate GH-responsive CYPs in rat hepatocytes. Some CYP enzymes are also regulated by the activator protein-1 (AP-1) complex and exogenous stresses, including oxidative components in the diet, can alter the cellular profile of AP-1 proteins via mitogen-activated protein (MAP) kinases and upstream signalling factors[9]. CYP regulation is altered is various diseases including obesity, diabetes and steatohepatitis and as there is a clear dietary link between diet and these diseases, it is plausible that dietary regulation of CYP enzymes may contribute towards pathogenic mechanisms.

Nutrients and CYP activity

A number of bioactive components in foods have been shown to modulate the activities of phase I biotransformation pathways by either inducing or inhibiting the CYPs which mediate these pathways (Table 1). Dietary factors may regulate those enzymes involved in activation of environmental chemicals or the enzymes that protect tissues against toxic metabolites.
Dietary fat
Dietary fat intakes may contribute to ongoing cellular damage in obesity and diabetes through the bimodal mechanism of upregulating pro-oxidant CYP enzymes, whilst increasing tissue levels of peroxidisable substrates[2]. High saturated fat diets have been shown to result in the induction of CYP2E1 protein and activity[10], with dietary intake of polyunsaturated fatty acids (from corn oil) increasing hepatic CYP2E1 activity to a greater extent[11], suggesting that the nature and quantity of dietary fat influences the upregulation of CYP2E1. Dietary induction of CYP2E1 may lead to lipid and protein peroxidation through the generation of free radicals during its catalysis, and increase exacerbations of any toxic effects of CYP2E1 metabolised xenobiotics such as ethanol or carbon tetrachloride. Studies have reported that enhanced peroxidation of polyunsaturated fatty acids present in fish oil resulted in upregulation resulted from an upregulation of CYP2E1 by lipid and ethanol and whilst free radical damage to the liver occurred, this was decreased by the antioxidant vitamin E[12].
Vitamin A
Animal in vitro studies have shown that vitamin A deficiency dysregulates GH-responsive CYPs in rat hepatocytes[6]. Specifically, pretranslational CYP2C11 is selectively down-regulated in vitamin A deficiency resulting in a reduction in circulating androgen levels, with dietary supplementation with the biological active form of the vitamin (all-trans-retinoic acid) preventing both the down-regulation of the enzyme and hormone[13, 14]. Other GH-regulated genes including CYP2C7[15] and CYP4A2[16] are also downregulated in vitamin A deficiency and several carotenoids have been shown to upregulate CYP1A gene expression, possibly through PXR mechanisms. Vitamin A deficiency also results in decreased expression of CYP26[17], with dose-dependent upregulation occurring in deficient animals supplemented with vitamin A[18].

Vitamin E
Dietary vitamin E supplementation selectively upregulates CYP2C11 protein and its associated androstenedione 16hydroxylase activity in rat liver and prevents the loss of microsomal CYP2C11 activity during lipid peroxidation[19]. It is also thought that vitamin E activates the PXR nuclear receptor which has an established role in xenobiotic CYP induction[20].
Specific foods and food groups
CYP3A4 is particularly susceptible to inhibition by bioactive compounds found in grapefruit and some other fruit juices, and it is recommended that such foods are not consumed when CYP3A4-metabolised medications (including codeine, cyclosporine, diazepam, erythromycin) are prescribed as this may result in intoxication[21].
Feeding studies using broccoli and brussels sprouts have reported increased expression and function of CYP1A1 and CYP1A2[22].
Altered drug metabolism of other medications, such as chlorzoxazone, has been shown with ingestion of watercress owing to inhibition of CYP2E1[23].
Other dietary components, including tea catechins[24], curcumin[25] and cabbage juice[26] have also been shown to modulate expression of CYP1A and CYP1B.

Vitamin D and CYP enzymes
CYP enzymes are responsible for the metabolism and catabolism of vitamin D (Table 2) with CYP27A1 and CYP27B1 being the main hydroxylase enzymes converting vitamin D to 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) respectively[27] (Figure 1). 1,25(OH)2D3 binds to the vitamin D receptor (VDR) present on numerous cells of the body triggering heterodimerisation with the retinoid X receptor (RXR). This complex is then translocated to the nucleus where it binds to vitamin D response elements (VDRE) in promoter regions of various genes, altering gene transcription. Non-genomic pathways of 1,25(OH)2D3 cell regulation have also been proposed. The transcription of CYP3A4, which is considered to be the most important of the drug-metabolising CYP enzymes, can be enhanced by 1,25(OH)2D3 via a VDR-mediated pathway. The primary sites of CYP3A4 expression are the liver and small intestine mucosa and it has been suggested that vitamin D via VDR helps to regulate CYP3A4 enzyme content in these tissues[28].
1,25(OH)2D3 CYP3A4 induction has been shown to affect the systemic exposure of orally administered drugs that are substrates of CYP3A4, such as atorvastatin, with vitamin D supplementation resulting in increased clearance of atorvastatin[29]. Furthermore, circulating levels of tacrolimus and sirolimus (CYP3A substrates) show cyclic variation throughout the year, corresponding to seasonal fluctuations in vitamin D status[30]. Therefore the regulation of CYP3A4 expression by vitamin D is a potential mechanism representing the interplay between xenobiotic and vitamin D metabolism[31].
Vitamin D is essential for calcium metabolism and mutations in CYP24A1 (vitamin D 24-hydroxylase) and CYP27B1 (25-hydroxyvitamin D 1-hydroxylase) result in idiopathic infantile hypercalcaemia and vitamin D dependent rickets type 1A or infantile hypocalcaemia respectively. Recent studies have also reported strong associations between CYP27B1 mutations and increased risk of multiple sclerosis[32].

Conclusion
Dietary composition may directly affect the activation of nuclear hormone receptors or influence ligand availability for their activation, depending upon the CYP enzyme being investigated. In addition, intermediates in signal transduction cascades may also respond to dietary components, such that dietary deficiency results in impaired responses. When studying the effects of nutrients on xenobiotic pathways, it would be useful to also search for the receptors and pathways whose activation induces expression of the genes involved in xenobiotic-metabolising enzymes[33].
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