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Cytochrome P450 Enzymes for the Synthesis of Novel and Known Drugs and Drug Metabolites
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sanjana Haque, Yuqing Gong, Sunitha Kodidela, Mohammad A. Rahman, Sabina Ranjit, Santosh Kumar
In the past five years, engineering mammalian CYP enzymes has been continually studied to produce pharmaceutical related products. Human CYP3A4 is responsible for about half of the CYP mediated drug metabolism in the body. Recently, an engineered human CYP3A4 (generated by site-directed mutagenesis) was studied using carbamazepine, a medication used in treatment of epilepsy and neuropathic pain. The mutants I369F, I369L, A370V, and A370L provided enhanced affinity and increased turnover of carbamazepine. The engineered CYP3A4 expressed higher carbamazepine binding and can be used as a CYP3A4-based electrochemical biosensor for determining carbamazepine in clinical samples (Muller et al., 2015). Human CYP3A4 was also engineered to alter its regio- and stereoselectivity. A CYP3A4 mutant A370I generated from random mutagenesis can be used to synthesize (R)-lisofylline, which cannot be generated by wild-type enzyme. The active metabolite (R)-lisofylline generated by engineered CYP3A4 is an anti-inflammatory substance, which shows efficacy on both type 1 diabetes treatment and hematopoiesis recovery. In addition, the engineered mutants I369F/L482F, I301F/I369F/L482F, and L211F/I301F/I369F/G481W/L482F generated from random mutagenesis approach showed the selectivity of oxidation in a theobromine derivative and sex hormone progesterone (Schiavini et al., 2017). Other human CYP enzymes have also been engineered to produce pharmaceutical products. For example, human CYP4A11, a fatty acid hydroxylase, was engineered to produce a blood pressure regulator 20-hydroxyeicosatetraenoic acid (20-HETE). A random mutagenesis was performed on CYP4A11 and yielded three improved CYP4A11 mutants, CP2600 (A24T/T263A), CP2601 (T263A), and CP2616 (A24T/T263A/V430E). The CYP4A11 mutant showed a threefold increase of expression in whole cells and >10-fold increase in purified proteins on the luminescence assay (Choi et al., 2013).
Pharmacological management of malignant hypertension
Published in Expert Opinion on Pharmacotherapy, 2020
Joanna Lewek, Agata Bielecka-Dąbrowa, Marek Maciejewski, Maciej Banach
The first studied drug is well-known but in a different group of patients [16]. Fenofibrate, one of the lipid-lowering drugs, has appeared to be effective in rats in which malignant hypertension was induced by the activation of a mouse renin gene by a natural xenobiotic indole-3-carbinol. In that experimental setting, fenofibrate lead to the suppression of renin-angiotensin system activity (suppression of renin gene expression, a reduction in plasma renin activity, and a reduction in plasma and kidney angiotensin II levels) [17]. However, there is no information whatsoever that the drug could be useful in human malignant hypertension. The hypothesis of this animal study was based on the fact that fenofibrate can increase the renal production of 20-hydroxyeicosatetraenoic acid (20-HETE) which is a product of the cytochrome P450 (CYP)-dependent ω-hydroxylase pathway [17]. Furthermore, 20-HETE, which is a tubular transport inhibitor, strengthens sodium excretion and prevents the development of Angiotensin II-dependent MHT. Fenofibrate led to the suppression of the activity of the renin-angiotensin system [17].
New potential modulators of CYP4F2 enzyme activity in angina pectoris: hsa-miR-24-3p and hsa-miR-34a-5p
Published in Biomarkers, 2020
Dovydas Gecys, Vacis Tatarunas, Audrone Veikutiene, Vaiva Lesauskaite
Eicosanoids are one of the most important biologically active molecules, which regulate inflammatory process. They are rapidly generated from arachidonic acid at sites of injury, and act on specific receptors to induce inflammation (Khanapure et al.2007, Capra et al. 2013, Dennis and Norris 2015). Biogenesis of eicosanoids starts with the synthesis of arachidonic acid from cell membrane phospholipids, followed by three major arachidonic acid metabolic pathways: cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (Calder 2010). According to the latest research, eicosanoid 20-hydroxyeicosatetraenoic acid (20-HETE) is one of the most important molecules involved in inflammatory process (Lasker et al.2000, Hoopes et al.2015, Kupstyte et al.2015). It is produced by ω-hydroxylase enzymes, encoded by CYP4A and CYP4F gene families (Lasker et al.2000).
Combined effect of telmisartan and fluvastatin on arachidonic acid metabolism in human liver microsomes
Published in Xenobiotica, 2018
Yuka Kato, Yuji Mukai, Anders Rane, Nobuo Inotsume, Takaki Toda
A limitation of this study was that we were unable to evaluate the effect of TEL and FLU on the production of 20-hydroxyeicosatetraenoic acid (20-HETE), which is one of the AA metabolites produced by CYP4A in the liver (Powell et al., 1998) and has a vasoconstrictive effect (Roman, 2002). The aim of this study was to evaluate the combined effect of TEL and FLU on metabolic pathways via CYP epoxidation, i.e., CYP2C9, CYP2C8 and CYP2J2. Since EETs and 20-HETE possess the inverse function on vascular homeostasis, the effect of both EETs and 20-HETE on vascular tone should be examined in further in vivo studies.