Introduction to Human Cytochrome P450 Superfamily
Shufeng Zhou in Cytochrome P450 2D6, 2018
The inhibition of human CYP activities can occur by three main mechanisms: reversible inhibition, mechanism-based inactivation (including quasi-irreversible and irreversible inhibition), and induction. Reversible inhibition refers to competition of two drugs for a CYP (Feng and He 2013; Fontana et al. 2005; Grime et al. 2009; Korzekwa 2014; Murray 1997; Riley et al. 2007; Zhou 2008b; Zhou et al. 2004, 2005, 2007; Zhou and Zhou 2009). Mechanism-based inhibition of CYPs involves the inactivation of the enzyme via the formation of metabolic intermediates that bind tightly and irreversibly to the enzyme. The metabolic intermediate can then exert its inhibitory effect by forming a direct covalent interaction with an amino acid in the active site, a noncovalent tight binding complex, or an inactive enzyme product that is released from the inhibitor. Mechanism-based inhibition of CYPs is characterized by NADPH-, time-, and concentration-dependent enzyme inactivation. A number of therapeutic drugs have been identified as mechanism-based CYP inhibitors. Mechanism-based inhibition of CYPs can decrease a drug’s first-pass clearance in the liver and gut, thus greatly altering the kinetic behavior. Moreover, the decrease in functional catalytic activity of the damaged CYP can lead to enhanced exposure of other drugs that are normally cleared by the CYPs, thus setting the stage for potential drug–drug interactions (Zhou et al. 2007; Zhou and Zhou 2009).
Biosynthetic Pathway of Artemisinin
Tariq Aftab, M. Naeem, M. Masroor, A. Khan in Artemisia annua, 2017
These two compartmentalized pathways of terpene biosynthesis communicate with each other to regulate metabolic intermediate availability. There are no absolute restrictions on the compartmentalization of intermediates in the pathways, and the degree of separation depends on the species and physiological conditions (Hampel et al., 2005). In A. annua, both the MVA and MEP seem to play a role in artemisinin production. When the cytosolic MVA is disrupted by inhibiting HMGR with mevinolin, artemisinin levels drop by about 80%. When DXR in the MEP is inhibited by fosmidomycin, artemisinin levels drop by about 70%. Use of both inhibitors leads to negligible artemisinin production in A. annua, suggesting that the two pathways interlink with each other to enhance this production (Towler and Weathers, 2007).
Dietary Substances Not Required in Human Metabolism
Luke Bucci in Nutrients as Ergogenic Aids for Sports and Exercise, 2020
In addition, many compounds are available that have not been tested by academic researchers. A partial list of such compounds includes α-ketoacids, ascorbyl palmitate, ATP, various individual or mixtures of individual amino acids, betaine (commonly referred to as trimethylglycine or TMG), boron, camosine, chlorophyll, cytochrome c, citrulline malate, colloidal silicates, dihydroepiandrostendione (DHEA), 6-keto-diosgenin, gamma hydroxybutyrate (GHB), glutathione, glandulars (dried raw animal organs), glycosaminoglycans, numerous herbs, lactate, lipoic acid (thioctic acid), NAD, pantetheine, pyruvate, plant sterols (e.g., ß-sitosterol), various protein hydrolysates, sarcosine, somatomedins, vanadium salts, various citric acid cycle intermediates, and almost any metabolic intermediate compound found in the human body. Each has a theoretical rationale for use, regardless of relevance to reality.
Numerical analysis of time-dependent inhibition kinetics: comparison between rat liver microsomes and rat hepatocyte data for mechanistic model fitting
Published in Xenobiotica, 2020
Chuong Pham, Swati Nagar, Ken Korzekwa
TDI experiments and subsequent modeling utilized a two-step incubation method: a primary preincubation with the inhibitor TAO at various concentrations and time points, followed by a secondary incubation with the substrate MDZ. Percent remaining activity (PRA) for each TAO concentration was plotted versus preincubation time. All experimental PRA plots showed a concave upward shape indicative of quasi-irreversible inhibition (Figures 2, 3 and 4) (Korzekwa et al., 2014). Using the RLM data to parameterize the quasi-irreversible kinetic scheme (Figure 1A), the model provided a better fit to the induced set compared to the uninduced set (R2: 0.973 and 0.962 respectively, Figure 2A and B, Table 2). However, the model poorly fit the 5 min preincubation data points (Figure 2A). The plot suggested a slight lag before inactivation. We hypothesized the lag was due to TAO n-dealkylation and oxidation before nitroso/heme MIC formation. Therefore, we applied a sequential (Seq) kinetic scheme adding inhibitor metabolite formation (M) prior to the metabolic intermediate complexation (E*, Figure 1B). The sequential model generated a better fit for the early preincubation times in RLM compared to the direct MIC formation model (Figure 2C and D), and a slightly better fit overall based on AICc (−DEX Direct: −166.1, Seq: −170.3; +DEX Direct: −116.5, Seq: −118.6).
Cumulus cell acetyl-CoA metabolism from acetate is associated with maternal age but only partially with oocyte maturity
Published in Systems Biology in Reproductive Medicine, 2022
Sharon Anderson, Peining Xu, Alexander J. Frey, Jason R. Goodspeed, Mary T. Doan, John J. Orris, Nicolle Clements, Michael J. Glassner, Nathaniel W. Snyder
Based on previous literature that CCs are highly glycolytic, produce pyruvate, and may be anticipated to use that pyruvate, we at first expected to see the utilization of glucose via pyruvate to generate the central metabolic intermediate acetyl-Coenzyme A (acetyl-CoA). Acetyl-CoA is the acyl-donor for protein and histone acetylation, the source of two-carbon units for de novo fatty acid and cholesterol synthesis, and a source of two-carbon units for oxidation in the TCA cycle (Trefely et al. 2020). However, initial experiments demonstrated that acetyl-CoA was poorly labeled by glucose and that acetate, not glucose or glutamine, was the preferred substrate to generate the central metabolic intermediate acetyl-CoA in the recovered CCs. Little is known about the metabolism of short-chain fatty acids like acetate in the CCs, despite the importance of acetate in the contexts of neuronal metabolism, liver metabolism, and cancer (Zhao et al. 2016; Trefely et al. 2020). Thus, based on the finding of relatively high acetate usage to generate acetyl-CoA, we examined the association between cumulus cell acetate metabolism to acetyl-CoA, maternal age, and oocyte maturity.
Mechanism-based inactivation of cytochrome P450 enzymes by natural products based on metabolic activation
Published in Drug Metabolism Reviews, 2020
Tingting Zhang, Jinqiu Rao, Wei Li, Kai Wang, Feng Qiu
MBI is closely correlated with metabolic activation. Mechanism-based inactivators can be biotransformed into electrophilic reactive species. On one hand, a chemically reactive metabolite can further covalently react with an amino acid residue in the active site and/or alkylate the heme prosthetic group in situ, resulting in irreversible inhibition of P450 enzymatic activity. For example, selegiline is a mechanism-based inactivator of CYP2B6, and the ketene intermediate of selegiline covalently modifies Asp64 of the enzyme (Sridar et al. 2012). Covalent modification of Thr302 by tert-butylphenylacetylene leads to MBI of CYP2B6 (Lin et al. 2011). Moreover, heme modification by reactive species also contributes to the MBI of P450 enzymes in some cases (Orr et al. 2012; Lin et al. 2017). On the other hand, a reactive intermediate may coordinate with the heme iron of P450 enzyme(s) and cause the formation of a metabolic-intermediate complex (MIC), which leads to quasi-irreversible inhibition of P450 enzymatic activity (Hirao et al. 2013).
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