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Inborn Errors of Metabolism
Published in Praveen S. Goday, Cassandra L. S. Walia, Pediatric Nutrition for Dietitians, 2022
Surekha Pendyal, Areeg Hassan El-Gharbawy
FAO provides as much as 80% of energy for heart and liver function. In the liver, the oxidation of fatty acids fuels the synthesis of ketone bodies which are utilized as an alternative energy source by extrahepatic organs, particularly the brain. Glucose is the preferred energy source in cells and glucose derived from glycogen is used during short-term fasting. During periods of prolonged fasting, febrile illness, or increased muscular activity, fatty acids are mobilized to meet the increased energy demands. The physiologically available fatty acids are mostly the C16 and C18 (long-chain) fatty acids and their oxidation requires entry into the mitochondrial matrix using enzymes of the carnitine shuttle (Figure 23.3, steps 1–3). Once inside the mitochondria, β-oxidation of the fatty acids occurs in a repeating cycle using the four enzyme complexes (Figure 23.3, steps 4–7), each “spiral” of the cycle releasing one molecule of acetyl-CoA and leaving a fatty acyl CoA two carbons shorter for recycling through further β-oxidation. Acetyl-CoA can then enter the citric acid (CA) cycle and/or serve as the precursor for ketone production. The reducing equivalents reduced nicotinamide adenine dinucleotide (NADH) and dihydroflavine adenine dinucleotide (FADH2) produced from β-oxidation and the CA cycle enter the electron transport chain for adenosine triphosphate (ATP) production.
Cell structure, function and adaptation
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Central to understanding many diseases is the appreciation that an oxygen-rich environment is potentially toxic and that protection against oxidant-induced stress is key to cell survival. The balance between oxidation and reduction is central to many processes including the reduction of ribose acids to generate deoxyribose, which is a critical component of DNA. Antioxidant enzymes are positioned throughout the cell to maximize protection. Superoxide dismutase 2 (SOD2) is located in mitochondria where it quickly takes reactive superoxide anions and converts them to the less potent hydrogen peroxide. This diffuses from mitochondria and can be destroyed by catalase. Within the soluble component of the cytoplasm (the cytosol) many peroxidases and transferases protect against oxidative species or make use of them in other cell reactions. Lipid peroxidation can occur as a chain reaction, as is seen in alcoholic liver disease (see Chapter 11), and there are many antioxidant enzymes associated with microsomes that can abort these reactions. In addition to enzymatic protection, which can also use hydrogen for reducing reactions, there are other molecules associated with reduced nicotinamide adenine dinucleotide (NADH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) that offer protection, notably the reduced tripeptide glutathione, uric acid, and vitamins E and C.
Enzymes
Published in S.J. Mulé, Henry Brill, Chemical and Biological Aspects of Drug Dependence, 2019
Recent studies in several laboratories have shown that liver microsomes contain NADPH-dependent (reduced nicotinamide adenine dinucleotide phosphate) enzyme systems which hydroxylate steroids such as estradiol, testosterone, etc.89 “94 Therefore, prolonged treatment with barbiturates may be paralleled by increased metabolism and decreased phsyiologocal action of steroids in vivo.95,96 Kuntzman97 has thoroughly reviewed this subject recently.
In vitro hepatic metabolism of the natural product quebecol
Published in Xenobiotica, 2023
Sigma-Aldrich (St. Louis, MO): dipotassium orthophosphate (K2HPO4), potassium dihydrogen orthophosphate (KH2PO4), magnesium sulphate (MgSO4), potassium carbonate (K2CO3), chlorzoxazone, enterolactone, thin layer chromatography (TLC) Silica gel 60 F254. Fisher Scientific (Ottawa, ON): acetonitrile (LC-MS grade), methanol (HPLC grade), formic acid (LC-MS grade), ethyl acetate (ACS grade), hexanes (ACS grade), tetrahydrofuran (ACS grade), magnesium chloride (MgCl2), sodium pyrophosphate decahydrate (SPP), D-saccharic acid 1,4-lactone monohydrate, uridine 5′-diphosphoglucuronic acid trisodium salt (UDP). Roche Diagnostics (Indianapolis, IN): reduced nicotinamide adenine dinucleotide (NADPH). Water was purified via a Millipore (Mississauga, ON) Milli-Q system with a Quantum EX Cartridge. Pooled human liver microsomes (HLM) and rat liver microsomes (RLM) were purchased from Gibco (Waltham, MA). Pooled human plasma (lithium heparin) was obtained from BioreclamationIVT (Westbury, NY). 2,2-Di-(3-methoxymethylphenyl)-1,3-propanediol (MMPPD) was prepared following literature procedures (Chênevert et al. 1999). Quebecol was prepared following a literature method (Pericherla et al. 2013) and is reported in supplementary information.
Effects of ticagrelor on the pharmacokinetics of rivaroxaban in rats
Published in Pharmaceutical Biology, 2020
Jia Chong, Hao Chen, Dapeng Dai, Shuanghu Wang, Quan Zhou, Junpeng Liu, You Lü, Hualan Wu, Minghui Du, Feifei Chen, Hui Jiang, Yunfang Zhou, Jiefu Yang
Rivaroxaban (purity >99%) and diazepam (purity >98%) were both purchased from J&K Scientific Ltd. (Beijing, China) (Figure 1). Rivaroxaban metabolite M2 (Lot No. 3530-047A1) was purchased from TLC Pharmaceutical Standards Ltd. (Newmarket, Ontario). Ticagrelor (purity > 98%) was purchased from Aladdin (Aladdin, Shanghai, China). Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was obtained from Roche Pharmaceuticals Ltd. (Basel, Switzerland). Acetonitrile and methanol were obtained from Fisher Scientific Co. (Fair Lawn, NJ, USA). Formic acid was got from Sigma-Aldrich (St. Louis, MO, USA). Ultrapure water was obtained from a Milli-Q water purification system (Millipore, Billerica, MA, USA). All other chemicals were of analytical grade or better.
Identification of novel glutathione conjugates of terbinafine in liver microsomes and hepatocytes across species
Published in Xenobiotica, 2019
Amol Patil, Mayurbhai Kathadbhai Ladumor, Shyam H Kamble, Benjamin M. Johnson, Murali Subramanian, Michael W. Sinz, Dilip Kumar Singh, Sivaprasad Putlur, Priyadeep Bhutani, Deepak Suresh Ahire, Saranjit Singh
TBF was purchased from Toronto Research Chemicals (Toronto, Canada). HPLC grade acetonitrile, formic acid, potassium dihydrogen phosphate and dipotassium hydrogen phosphate salts were purchased from Merck Specialties Private Limited (Mumbai, India). Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was purchased from Sisco research laboratory limited (Mumbai, India). Mixed gender liver microsomes (human) or male liver microsomes (rat, mouse, dog, monkey) were purchased from Corning (New York, USA). Cryopreserved male hepatocytes (human, mouse, dog, monkey) were obtained from Bioreclamation IVT. Rat hepatocytes were freshly isolated using an in-house protocol (Subramanian et al., 2014).