liver cytochrome

BMS-903452 is a potent and selective GPR119 agonist with an EC50 of 14 nM, indicated for the treatment of acute and chronic rodent diabetes. GPR119 is mainly expressed in pancreatic b cells and gastrointestinal endocrine cells. BMS-903452 shows no significant inhibitory effect on 9 cytochrome P450 enzymes (IC50 > 40 μM), does not activate PXR (EC50 > 50 μM), and is not toxic to liver (HEPG2) cell lines.

Tegafur (FT 207) is a congener of the antimetabolite fluorouracil with antineoplastic activity. Tegafur is a prodrug that is gradually converted to fluorouracil in the liver by the cytochrome P-450 enzyme.

Clomethiazole (Distraneurin) is an orally active GABAA agonist and it is an anticonvulsant agent. It also has the potential for treating convulsive status epilepticus. Chlormethiazole inhibits cytochrome P450 isoforms: CYP2A6 and CYP2E1 in human liver microsomes.

Protoporphyrin IX (PPIX) is a tetrapyrrole that is a metabolic precursor of heme, cytochrome c, and chlorophyll. Protoporphyrin IX has been shown to improve liver function, promote cellular tissue respiration, improve protein and glucose metabolism, and resist complement binding.

Mefentrifluconazole is a potent, selective and orally active fungal CYP51 (Kd= 0.5 nM) inhibitor, but shows less inhibitory activity on human aromatase (IC50=0.92 μM). Mefentrifluconazole is a novel azole derivative and used as an agrochemical broad-spectrum antifungal agent.

Atorvastatin, an orally active HMG-CoA reductase inhibitor, effectively lowers blood lipids by activating liver cytochrome p450 to accelerate metabolism. Atorvastatin inhibits the proliferation and invasion of human SV-SMC cells with IC50 values of 0.39 μM and 2.39 μM, respectively. [Atorvastatin] combined with clopidogrel may lead to increased thrombotic events in patients.

Phoxim is an organophosphate insecticide that inhibits acetylcholinesterase (AchE) activity in the nervous system of insects. It is used in veterinary medicine for the treatment of ectoparasitic mites. It is toxic to aquatic organisms and may affect cytochrome P450 enzyme (CYP1A) activity and its expression levels in fish liver microsomes. In addition, sub-lethal doses of phoxim affected detoxification enzyme activities of adult mulberry whitefly, such as changes in the activities of glutathione S-transferase (GST), carboxylesterase (CarE) and acetylcholinesterase (AchE).

Hydroxy desmethyl Bosentan (Ro 64-105) is a metabolite of Bosentan formed by the liver cytochrome P450 enzymes CYP2C9 and CYP3A4.

O-Desmethyl Midostaurin is the active Midostaurin metabolite via cytochrome P450 liver enzyme metabolism.

Cevimeline hydrochloride hemihydrate ((-)-SNI-2011), a novel muscarinic receptor agonist, is being explored as a potential treatment for xerostomia in Sjogren's syndrome, exhibiting an IC50 value indicative of its affinity for mAChR. This compound's pharmacological effects on the gastrointestinal, urinary, and reproductive systems, alongside its impact on various tissues, were thoroughly examined in species including mice, rats, guinea pigs, rabbits, and dogs. The metabolic breakdown of (-)-SNI-2011 was studied in vitro using rat and dog liver microsomes to assess its biotransformation. Upon oral administration, peak plasma concentrations were reached within an hour in both rats and dogs, showcasing rapid absorption and a subsequent decrease in concentration with a half-life ranging from 0.4 to 1.1 hours. Bioavailability was noted at 50% in rats and 30% in dogs. Metabolic pathways highlighted significant species differences, with both S- and N-oxidized metabolites identified in rats, but only N-oxidized metabolites in dogs. Additionally, gender differences in pharmacokinetics were observed in rats but were absent in dogs. In vitro studies pinpointed the involvement of cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO) in the metabolism of (-)-SNI-2011, specifically through sulfoxidation and N-oxidation processes, respectively. CYP2D and CYP3A were identified as the primary enzymes responsible for sulfoxidation in rat liver microsomes.

(+)-Cevimeline hydrochloride hemihydrate ((+)-SNI-2011), a potent muscarinic receptor agonist, shows promise as a therapeutic candidate for xerostomia in Sjogren's syndrome. It exhibits a broad pharmacological profile across various systems in animal models including mice, rats, guinea pigs, rabbits, and dogs. Metabolism studies using rat and dog liver microsomes reveal rapid absorption with peak plasma concentrations (Cmax) within one hour post-oral administration and a half-life (t1 2) between 0.4 to 1.1 hours. Bioavailability is 50% in rats and 30% in dogs. Metabolic analysis shows species-specific differences: rats produce S- and N-oxidized metabolites, while dogs produce only N-oxidized metabolites. Sex-based pharmacokinetic differences were noted in rats but not in dogs. In vitro studies indicate cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO) involvement in the sulfoxidation and N-oxidation of SNI-2011, with CYP2D and CYP3A mainly responsible for sulfoxidation in rat liver microsomes.

Hydroxy bosentan (Ro 48-5033) is a primary metabolite of Bosentan (BOS) metabolized by the cytochrome P450 system in the liver, assisting BOS pharmacologically with 10%-20% activity retention.

Antifungal agent 114 (Compound 19g) serves as an inhibitor of Cytochrome P450 (Cytochrome P450), effectively suppressing CYP2C9, CYP2C19, CYP2D6, and CYP3A4 at 10 μM. It exhibits antifungal activity against Cryptococcus neoformans, Candida, and Aspergillus, with an MIC of less than 0.0625 μg mL. Additionally, Antifungal agent 114 demonstrates favorable metabolic stability in human liver microsomes with a half-life of 107 minutes.

SM 12502 serves as a substrate for cytochrome P450 2A6 in human liver microsomes.

TG-100435 is a novel multi-target oral protein tyrosine kinase inhibitor. The metabolic flux of TG100435 is entirely inhibited by methimazole and ketoconazole. In human liver microsomes or recombinant P450, the formation of TG100435 increases with the activity of cytochrome P450 reductase, suggesting that cytochrome P450 reductase may be involved.

Octachlorodibenzo-p-dioxin (OCDD) is an environmental contaminant with no acute toxicity when administered. In rats, the systemic elimination half-life of Octachlorodibenzo-p-dioxin (50 μg kg intravenously or 50-5000 μg kg orally) is 3-5 months. It can accumulate and concentrate in the liver and adipose tissue after low-dose, repeated exposure. Repeated dosing of Octachlorodibenzo-p-dioxin leads to increased activity of 7-ethoxyresorufin-O-deethylase (7-EROD) and elevated total cytochrome P-450 levels.

Erythromycin glutamate is a macrolide bacteriostatic antibiotic. This antibiotic is metabolized through the liver and inhibits cytochrome enzyme P450A 3A41.

(±)14(15)-EET is a metabolite of arachidonic acid that is formed via epoxidation of arachidonic acid by cytochrome P450.[1],[2] It prevents increases in leukotriene B4, ICAM-1, and chemokine (C-C motif) ligand 1 (CCL2) induced by oxidized LDL in primary rat pulmonary artery endothelial cells (RPAECs) when used at a concentration of 1 μM.[3] (±)14(15)-EET induces dilation of preconstricted isolated canine coronary arterioles (EC50 = 0.2 pM).[4] It reduces myocardial infarct size as a percentage of the area at risk in a canine model of ischemia-reperfusion injury induced by left anterior descending coronary artery (LAD) occlusion when administered at a dose of 0.128 mg kg prior to occlusion or reperfusion.[5] Reference:[1]. Chacos, N., Falck, J.R., Wixtrom, C., et al. Novel epoxides formed during the liver cytochrome P-450 oxidation of arachidonic acid. Biochem. Biophys. Res. Commun. 104(3), 916-922 (1982).[2]. Oliw, E.H., Guengerich, F.P., and Oates, J.A. Oxygenation of arachidonic acid by hepatic monooxygenases. Isolation and metabolism of four epoxide intermediates. J. Biol. Chem. 257(7), 3771-3781 (1982).[3]. Jiang, J.-X., Zhang, S.-J., Xiong, Y.-K., et al. EETs attenuate ox-LDL-induced LTB4 production and activity by inhibiting p38 MAPK phosphorylation and 5-LO BLT1 receptor expression in rat pulmonary arterial endothelial cells. PLoS One 10(6), e0128278 (2015).[4]. Oltman, C.L., Weintraub, N.L., VanRollins, M., et al. Epoxyeicosatrienoic acids and dihydroxyeicosatrienoic acids are potent vasodilators in the canine coronary microcirculation. Circ. Res. 83(9), 932-939 (1998).[5]. Nithipatikom, K., Moore, J.M., Isbell, M.A., et al. Epoxyeicosatrienoic acids in cardioprotection: Ischemic versus reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 291(2), H537-H542 (2006).

Aflatoxin G1-13C17is intended for use as an internal standard for the quantification of aflatoxin G1by GC- or LC-MS. Aflatoxin G1is a mycotoxin that has been found inA. terricola.1In vivo, aflatoxin G1is lethal to ducklings (LD50= 1.18 mg/kg).2It induces hepatocellular carcinoma tumor formation and lethality in rats when administered at doses of 1.4 and 3 mg/animal, respectively. Aflatoxin G1also inhibits liver and kidney succinate dehydrogenase and fumarase, as well as kidney cytochrome oxidase, NADH oxidase, α-glycerophosphate dehydrogenase, isocitrate dehydrogenase, and malate dehydrogenase in rats.3 1.Moubasher, A.H., el-Kady, I.A., and Shoriet, A.Toxigenic Aspergilli isolated from different sources in EgyptAnn. Nutr. Aliment.31(4-6)607-615(1977) 2.Wogan, G.N., Edwards, G.S., and Newberne, P.M.Structure-activity relationships in toxicity and carcinogenicity of aflatoxins and analogsCancer Res.31(12)1936-1942(1971) 3.Bai, N.J., Pai, M.R., and Venkitasubramanian, T.A.Mitochondrial function in aflatoxin toxicityIndian J. Biochem. Biophys.14(4)347-349(1977)

trans-Hydroxy Glimepiride is an active metabolite of the sulfonylurea glimepiride, formed primarily in the liver by the cytochrome P450 (CYP) isoform CYP2C9.

N-Desmethyl Eletriptan, a metabolite of eletriptan, is primarily formed from eletriptan by the cytochrome P450 (CYP) isoform CYP3A4 in human liver microsomes.

22-HDHA is an oxidation product of docosahexaenoic acid (DHA).

Cytochrome P450 metabolites of arachidonic acid, such as 11(12)-EpETrE and 14(15)-EpETrE have been identified as endothelium derived hyperpolarizing factors with vasodilator activity. Soluble epoxide hydrolase (sEH) catalyzes the conversion of EpETrEs to the corresponding DiHETrEs thereby diminishing their activity. Inhibitors of sEH may therefore have clinical utility for treating hypertension and systemic inflammation. S-NEPC is a colorimetric substrate used to measure sEH activity. It also is a substrate for Glutathione S-transferase, microsomal epoxide hydrolase and porcine liver carboxylesterase. Hydrolysis of S-NEPC by sEH yields 4-nitrophenol which can be quantified spectrophotometrically at 405 nm. S-NEPC is adaptable for use in 96-well microwell plate readers.

5-hydroxy Propranolol is a metabolite of propranolol , a β-adrenergic receptor antagonist. Propranolol is primarily metabolized in the liver, with cytochrome P450 isoform 2D6 directing ring hydroxylation and the generation of 5-hydroxy propranolol and related metabolites.