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Carbohydrate metabolism
Published in Martin Andrew Crook, Clinical Biochemistry & Metabolic Medicine, 2013
Non-glucose-reducing substances are identified by chromatography and specific tests. The significance of a Clinitest-positive result varies with the substances, which are as follows. Glucose.Glucuronates are relatively common urinary reducing substances. Numerous drugs, such as salicylates and their metabolites, are excreted in the urine after conjugation with glucuronate in the liver.Galactose is found in the urine in galactosaemia.Fructose may appear in the urine after very large oral doses of sucrose, or after excessive fruit ingestion, but usually fructosuria is due to one of two rare inborn errors of metabolism, both transmitted as autosomal recessive disorders: – essential fructosuria is usually a benign condition (hepatic fructokinase deficiency),– hereditary fructose intolerance is characterized by hypoglycaemia that may lead to death in infancy.Lactose. Lactosuria may occur in: – late pregnancy and during lactation,– lactase deficiency.Pentoses. Pentosuria is very rare. It may occur in: – alimentary pentosuria, after excessive ingestion of fruits such as cherries and grapes – the pentoses are arabinose and xylose,– essential pentosuria, a rare recessive disorder due to L-xylulose reductase deficiency, characterized by the excretion of xylose – it is usually benign.Homogentisic acid appears in the urine in the rare inborn error alkaptonuria. It is usually recognizable because it forms a blackish precipitate in urine on standing. Urea and creatinine may give weak positive results at high concentrations.
Nasal odorant metabolism: enzymes, activity and function in olfaction
Published in Drug Metabolism Reviews, 2019
Jean-Marie Heydel, Philippe Faure, Fabrice Neiers
In addition to CYPs and GSTs, other XMEs were shown to be able to metabolize odorants and to be expressed in the OE such as UDP-glucuronosyltransferases (UDPGTs; Table 3) (Lazard et al. 1991; Leclerc et al. 2002; Minn et al. 2002; Heydel et al. 2010; Thiebaud et al. 2010). UDPGTs are expressed in the human fetal OE (indicated by quantitative RT-PCR), and the 2A1 isoform (UGT2A1) is preferentially expressed in the OE (Zhang et al. 2005). UGT2A1 was also shown to be expressed in the mucus secreted by Bowman’s glands, suggesting that it is present in the mucus even though this expression has not yet been detected (Lazard et al. 1991). Many additional metabolizing enzymes were found in the OE and mucus (Tables 4–6). Only a few of these enzymes were shown to metabolize odorants such as dicarbonyl L-xylulose reductase (Zaccone et al. 2015; Robert-Hazotte et al. 2019a) or sulfotransferase (Tamura et al. 1997). Two specific types of enzymes were found in abundance: alcohol dehydrogenases and aldehyde dehydrogenases (Tables 4 and 5). Additionally, some of these types of enzymes, such as aldehyde dehydrogenase 7, are preferentially expressed in the OE (Zhang et al. 2005).
Bioactivation of diclofenac in human hepatocytes and the proposed human hepatic proteins modified by reactive metabolites
Published in Xenobiotica, 2020
Kazuko Inoue, Hitoshi Mizuo, Tomomi Ishida, Takafumi Komori, Kazutomi Kusano
In this study, the preference of target proteins for covalent binding, depending on the type of reactive metabolites of diclofenac, such as quinone-imine intermediates and acyl glucuronides, was also shown. The CYP inhibitor, 1-ABT, affected covalent modification by 14C-diclofenac in human hepatocytes; seven of the nine radioactive protein spots (spots 1, 3, 4, 5, 6, 7 and 8) were no longer covalently modified by 14C-diclofenac (Figure 4). This indicated that these proteins could be modified by the oxidative reactive metabolites of diclofenac generated by CYPs, as shown in Figure 1. In contrast, spots 2 and 9 remained radioactive after the incubation of 14C-diclofenac with human hepatocytes in the presence of 1-ABT (Figure 4(b)). This indicated that proteins in spot 2 (human serum albumin and heat shock protein) and spot 9 (glutathione S-transferase α2, L-xylulose reductase, and glutathione S-transferase κ1) might be modified by the acyl glucuronides of diclofenac. Although dipeptidyl peptidase IV was reported as a putative target protein of acyl glucuronide of diclofenac in rats (Hargus et al., 1995), human serum albumin, heat shock 70 kDa protein 1 A/1B, GST α2, L-xylulose reductase, and GST κ1 were supposed to be the major target proteins of reactive acyl glucuronide of diclofenac in human, possibly via imine formation with the lysine residues of the protein in human hepatocytes (Ding et al., 1993; Hammond et al., 2014). Acyl glucuronides of NSAIDs have been reported to bind to human serum albumin, although there is no evidence that covalent modification of human serum albumin by diclofenac can cause hypersensitivity in humans (Benet et al., 1993). Acyl glucuronides can also bind to DNA implying that they would prefer to bind hard nucleophilic amine groups present on macromolecules (Sallustio et al., 2006). Not only acyl glucuronide but also S-CoA adduct formation could also involve in covalent binding to proteins, because S-CoA metabolites of NSAIDs were reported as more reactive metabolite than acyl glucuronide leading to modification of human liver microsomal proteins (Darnell et al., 2015). To confirm involvement of acyl glucuronide of diclofenac in covalent binding to protein, a UGT inhibitor should also be used, although a UGT inhibitor, borneol, also inhibited CYP activity to form oxidative reactive metabolites of diclofenac in human hepatocytes (Jinno et al., 2014). Further investigation to optimize the experimental conditions for UGT inhibition in human hepatocytes should be needed.