Evaluation of the Dermal Irritancy of Chemicals
David W. Hobson in Dermal and Ocular Toxicology, 2020
Over 700 enzymes have been isolated, each capable of catalyzing a specific organic or inorganic reaction. Some enzymes are found only in specific organs, while others are found in most every cell of the body. Enzymes may also be quite specific to certain compartments or organelles within the cells, such as cytosol, lysosomes, peroxisomes, membrane border, nucleus or nucleolus, endoplasmic reticulum, Golgi bodies, or mitochondria. Enzymes common to many or most organs of an individual animal may exist in different forms, which demonstrate dissimilar patterns on electrophoresis. Different forms of the same enzyme are called isozymes, or, more preferably, isoenzymes. Levels of enzymes in body fluids usually have a “normal” range which often varies with species, age, sex, etc., and may vary from one individual animal to another. Using blood, one or more baseline levels may be obtained prior to any procedure. Increased levels of enzymes may be due to leakage from injured or dying cells, or due to increased synthesis as a result of damage or tissue insult or an increase in the number or activity of cells producing the enzyme.
Plasma enzymes in diagnosis (clinical enzymology)
Martin Andrew Crook in Clinical Biochemistry & Metabolic Medicine, 2013
The diagnostic precision of plasma enzyme analysis may be improved by the following: Serial enzyme estimations The rate of change of plasma enzyme activity is related to a balance between the rate of entry and the rate of removal from the circulation. A persistently raised plasma enzyme activity is suggestive of a chronic disorder or, occasionally, impaired clearance.Isoenzyme determination Some enzymes exist in more than one form; these isoenzymes may be separated by their different physical or chemical properties. If they originate in different tissues, such identification will give more information than the measurement of plasma total enzyme activity; for example, CK may be derived from skeletal or cardiac muscle, but one of its isoenzymes is found predominantly in the myocardium.Estimation of more than one enzyme Many enzymes are widely distributed, but their relative concentrations may vary in different tissues. For example, although both ALT and AST are abundant in the liver, the concentration of AST is much greater than that of ALT in heart muscle.
Isoform Definition of Muscle Machines
Peter W. Hochachka in Muscles as Molecular and Metabolic Machines, 2019
But what is the role of isoform-based fiber-type differentiation in this racing car version of vertebrate muscle? Interestingly, this is where the penny drops. As in other good avian flyers, hummingbird flight muscle is formed exclusively of one fiber type, fast-twitch oxidative (FOG) or type Ha fibers. Electron microscopy indicates remarkable cell-to-cell homogeneity, each muscle cell essentially identical to its neighbor. Although detailed isozyme studies have not been performed, at least one isozyme system has been examined—lactate dehydrogenase. Unlike the isozyme patterns often found in FOG fibers (dominated by M subunits), the LDH isozyme complex in hummingbird flight muscles has evolved toward one dominant band (the H4 isozyme), with a modest amount of a second band (the H3M1 band), indicating residual expression of the M gene in this tissue, exactly as in hummingbird heart (Hochachka et al., 1992). On the assumption that fiber ultrastructural homogeneity also implies homogeneity (or constant expression) of isoform components, we can tentatively conclude that in designing the most metabolically active muscle found among the vertebrates, evolution seems to have selected for a unique combination of component isoforms at the expense of all other possibilities. Instead of taking advantage of a seemingly enormous potential for making different kinds of muscle types, nature seems to opt for the exact opposite strategy.
Evaluation of the effect of Bovis Calculus Artifactus on eight rat liver cytochrome P450 isozymes using LC-MS/MS and cocktail approach
Published in Xenobiotica, 2021
Yun-Jing Zhang, Wen-Li Zhou, Fei Yu, Qian Wang, Can Peng, Jia-Yi Kan
However, there are differences between species in the homotype composition, expression and catalytic activity of drug metabolic enzymes and the use of human liver microsomes would have made more sense to predict clinical drug–drug interactions (DDIs). Also, even when the amino acid sequences are highly identical between the isozymes, this does not automatically mean similar catalytic specificity. Therefore cautions should be applied when extrapolating the results to humans (Martignoni et al. 2006) and the use of human liver microsomes would have made more sense to predict human DDIs. And in vitro studies cannot simulate the real physiological environment. Cautions should be applied when extrapolating the results to humans. A more comprehensive investigation should therefore be performed in the future by using human liver microsomes and in vivo studies.
Investigation of the effects of cephalosporin antibiotics on glutathione S-transferase activity in different tissues of rats in vivo conditions in order to drug development research
Published in Drug and Chemical Toxicology, 2020
Fikret Türkan, Zübeyir Huyut, Parham Taslimi, Mehmet Tahir Huyut, İlhami Gülçin
Glutathione S-transferases (GST) are ubiquitous multifunctional enzymes and represent 10% of cytosolic proteins which catalyze the conjugation of toxic xenobiotics and oxidatively produced compounds, thus facilitate their metabolism, removal and provide protection against oxidants (Halliwell 2009, Mazzetti 2015). There are three major families that exhibit GST activities are cytosolic, mitochondrial, and microsomal. (Hayes et al.2005) Cytosolic GSTs consist family of detoxification enzymes that function as homo or heterodimers and are sorted seven classes named as alpha (α), mu (μ), theta (θ), pi (π), zeta (ζ), chi (χ), and sigma (σ) (Strange et al.2001, Oakley 2011). The mostly expressed in mammalian tissues are Pi (GSTP), Mu (GSTM), and Alpha (GSTA) (Egaas et al.1995, Gopal et al.2000, Wu and Dong 2012). The pattern of expression of these isozymes is specific for species, age, and organs (Rowe et al.1997). These enzymes also show variable expression toward certain highly reactive chemical contaminants and remarkable affect on resistance/sensitivity to chemical toxicities. Variations in GST isozyme expression effect on health. For example, low expression of human GSTM is related to a rised incidence of bladder (Daly et al.1993) and colon cancer (Gopal et al.2000). Therapies that increase the expression of GST isozymes may be useful in disease prevention. Therefore, it is very important to increase or protect the in vivo activity of this enzyme.
Aldehyde oxidase mediated drug metabolism: an underpredicted obstacle in drug discovery and development
Published in Drug Metabolism Reviews, 2022
Siva Nageswara Rao Gajula, Tanaaz Navin Nathani, Rashmi Madhukar Patil, Sasikala Talari, Rajesh Sonti
The first and foremost factor for the underprediction is the species difference. There are vast differences in AO isozyme’s expression ranging from the absence of expression in dogs, cats, and pigs; to one active isozyme in humans and chimpanzees; four isozymes in rats, mice, and rabbits (Beedham et al. 1987; Sahi et al. 2008). Reports have shown that no single species can reliably predict AO-metabolism for all AO-substrates. Hence, a preclinical animal model to human extrapolation is inaccurate (Garattini and Terao 2012). Also, there are significant differences in activity between various species in mice and rats. When 12 different strains of rats were tested for AO activity, the highest activity was found in Sea:SD rats, whereas the lowest activity was found in WKA/Sea rats (Sugihara et al. 1995). Dalvie et al. performed both in vivo and in vitro zoniporide metabolism studies. In vivo study showed that zoniporide metabolized to 2-oxozoniporide by AO, which was observed in humans and rats but completely absent in dogs (Dalvie et al. 2010). In vitro study conducted on the S9 fraction across species and strain showed a great difference in the formation of 2-oxozoniporide (Dalvie et al. 2013).
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