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Direct Oral Anticoagulants: New Options
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
In addition, the action of VKA is modified by manifold interactions with drugs and food (Alban, 2013). Co-administered substances can either induce or inhibit the VKA metabolising cytochrome P450 isoenzymes (i.e., CYP2C9, CYP3A4, CYP1A2) or can reduce the high plasma protein binding of VKA (99%). Besides these pharmakokinetic mechanisms, there are also pharmacodynamics interactions. The action and thus the bleeding risk are, of course, enhanced by other antithrombotics, but also by compounds reducing the coagulation factor synthesis or by reducing the availability of vitamin K (e.g., antibiotics impairing the microbiome). Additionally, the vitamin K content of food modulates the anticoagulation by VKA. In fact, whenever another drug is applied, the potential of an interaction with VKA has to be considered. The relevance of interactions between VKA and other drugs is illustrated by the finding that about one-third of the patients under VKA with bleedings leading to hospitalization were taking other interacting drugs (Schmiedl et al., 2013). It is important to note that 74% of these concomitantly used drugs cause pharmacodynamic and not pharmacokinetic interactions and thus have no influence on the INR (Schmiedl et al., 2013) (see Section 9.5.7).
Will Systems Biology Transform Clinical Decision Support?
Published in Paul Cerrato, John Halamka, Reinventing Clinical Decision Support, 2020
Genome. Equally important are possible interactions among these components and their impact on human physiology. For example, among persons exposed to coffee, there is evidence to suggest that consumption of large quantities increases the risk of cardiovascular disease.15,16 But a large-scale study that evaluated over 9 million individuals included in the UK Biobank cohort indicates a more nuanced interpretation of the research. It calculated hazard ratios (HR) for coffee intake and overall mortality to determine if caffeine metabolism, as influenced by single nucleotide polymorphisms (SNPs), including AHR, CYP1A2, CYP2A6, and POR, would affect the likelihood of death. On a 10-year follow-up, the analysis found that coffee consumption actually lowered the risk of death. Loftfield et al. concluded: “[T]he HRs for 6 or more cups per day ranged from 0.70 (95% CI, 0.53–0.94) to 0.92 (95%CI, 0.78–1.10), with no evidence of effect modification across strata of caffeine metabolism score.”17 In other words, the caffeine in coffee has no adverse effect on cardiovascular status for healthy individuals, regardless of whether they are slow or fast metabolizers, as indicated by their genetic makeup. From a systems biology perspective, the take home message is: A study of the interaction between the exposome and the genome eliminates caffeine as a likely contributor to cardiovascular disease, allowing investigators to look to some other ingredient in coffee as a possible culprit.
Lead Toxicity and Flavonoids
Published in Tanmoy Chakraborty, Lalita Ledwani, Research Methodology in Chemical Sciences, 2017
Amrish Chandra, Deepali Saxena
“Naringenin”, a flavanoid found in grapefruit juice, has been shown to have an inhibitory effect on the human cytochrome P450 isoform CYP1A2 that can change pharmacokinetics in a human (or orthologous) host of several popular drugs in an adverse manner, even resulting in carcinogens of otherwise harmless substances.5 Naringenin (Fig. 17.1) is considered to have a bioactive effect on human health as antioxidant, free radical scavenger, anti-inflammatory, carbohydrate metabolism promoter, and immune system modulator. This substance has also been shown to reduce oxidative damage to DNA in vitro. Scientists exposed cells to 80 μmol of naringenin per liter, for 24 h, and found that the amount of hydroxyl damage to the DNA was reduced by 24% in that very short period of time. A full glass of orange juice will supply about enough naringenin to achieve a concentration of about 0.5 μmol/L.
Toxicological and pharmacokinetic properties of sucralose-6-acetate and its parent sucralose: in vitro screening assays
Published in Journal of Toxicology and Environmental Health, Part B, 2023
Susan S. Schiffman, Elizabeth H. Scholl, Terrence S. Furey, H. Troy Nagle
Inhibition of CYP1A2 by sucralose-6-acetate may also potentially increase plasma concentrations of pharmaceuticals that are CYP1A2 substrates. Representative CYP1A2 substrates (along with their biological functions/indications) include alosetron (irritable bowel syndrome), axitinib (renal cell carcinoma), caffeine (CNS stimulant), clozapine (antipsychotic), flutamide (prostate cancer), frovatriptan (migraine), melatonin (sleep-wake cycle), mexiletine (heart arrhythmias), mirtazapine (antidepressant), olanzapine (antipsychotic), rasagiline (Parkinson’s disease), tacrine (Alzheimer’s disease), theophylline (bronchodilator), tizanidine (muscle relaxer), and triamterene (diuretic). Inhibition of CYP2C19 by sucralose-6-acetate might potentially elevate plasma concentrations of CYP2C19 substrates. Representative CYP2C19 substrates that are known to be significantly affected by CYP2C19 inhibitors (along with their biological functions/indications) include abrocitinib (atopic dermatitis), cannabidiol (seizures), carisoprodol (muscle relaxant), cilostazol (claudication), citalopram (antidepressant), clobazam (sedative), clopidogrel (blood thinner), diazepam (anxiety), esomeprazole (gastroesophageal reflux), methadone (narcotic addiction), omeprazole (gastroesophageal reflux), phenytoin (seizures), and tofacitinib (rheumatoid arthritis) (DrugBank 2022; PubChem 2022).
Whole-cell bioreporters for evaluating petroleum hydrocarbon contamination
Published in Critical Reviews in Environmental Science and Technology, 2021
Bo Jiang, Yizhi Song, Zengjun Liu, Wei E. Huang, Guanghe Li, Songqiang Deng, Yi Xing, Dayi Zhang
Similarly, although toxicity WCBs are intrinsically responsive to general toxicities of contaminants and demonstrate no specificity for petroleum hydrocarbons, some genotoxicity WCBs are specifically designed for PAHs, pertaining their metabolic pathways. PAHs are regarded as indirectly DNA-damaging reagents, which are oxidized into epoxide or benzoquinone by the cytochrome P450 (CYPs) monooxygenase in mammalian cells. Epoxide or benzoquinone can further interact with cellular DNA and form DNA-adducts, behaving genotoxic to cells (Hakkola et al., 1996). CYPs are monooxygenases universally found in many mammalian cells, which are encoded by CYP1A1 or CYP1A2 and catalyze many reactions involved in the degradation of endogenous substrates, and some CYP expression is induced by PAHs (Hakkola et al., 1996). Accordingly, exogenous addition of CYPs is commonly used in WCBs to sense the genotoxicity of PAHs. For example, Göran et al. investigated the genotoxicity of 8 chlorinated aromatic hydrocarbons in Salmonella/microsome assays and found that they only possessed genotoxicity in the presence of CYPs (Löfroth, Nilsson, Agurell, & Sugiyama, 1985). Song et al. also found a higher response ratio of ADPWH_recA WCB to benzo[a]pyrene in the presence of S9, which acts as a P450 metabolic activation mixture (Song et al., 2009). Alternatively, some well-characterized CYP enzymes are also found in bacteria, e.g., CYP101 (P450cam) from Pseudomonas putida (Poulos, Finzel, & Howard, 1987), CYP102 (P450BM-3) from Bacillus megaterium (Ravichandran, Boddupalli, Hasermann, Peterson, & Deisenhofer, 1993) and P450 CYP153 from Alcanivorax borkumensis SK2 (Kubota et al., 2005; van Beilen et al., 2006). CYP enzymes in these bacterial strains can be further engineered to enhance the oxidation activity for PAHs (Carmichael & Wong, 2001), enabling these strains to be potentially used as the hosts for WCB construction, without the requirement of exogenous supplement with CYPs.