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Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Different patterns of drug toxicity between adult and paediatric patients is not confined to the neonate. There are numerous examples of both different ADRs and different incidences of ADRs in children as opposed to adults [2]. The mechanism behind the increased incidence of certain ADRs in children is unknown. In contrast, there are some ADRs that are more common in adults than children. Hepatotoxicity following paracetamol overdose is a significant problem in adults, but is infrequent in pre-pubertal children. This difference appears to be related to an enhanced capacity for sulphation in children.
Renal Drug-Metabolizing Enzymes in Experimental Animals and Humans
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Usually the biological activity of a substance is reduced by sulfation. However, this is not always the case. Certain sulfate conjugates of morphine, e.g., morphine 6-sulfate, are considerably more active as an analgesic than the parent compound when injected intraventricularly (Brown et al., 1985). There is also increasing evidence that sulfation may enhance the toxicity of certain chemicals for instance, N-hydroxy-2-acetylaminofluorene (see reviews by Miller et al. [1985] and Mulder et al. [1988]). Sulfation of the carcinogen 5-hydroxymethyl-chrysene (5-HCR) to the active metabolite 5-HCR sulfate occurs in renal cytosol from rats, mice, guinea pigs, and hamsters, although the activity is highest in females of the latter two species (Okuda et al., 1989).
Biochemical Basis of Cervical Maturation
Published in Gabor Huszar, The Physiology and Biochemistry of the Uterus in Pregnancy and Labor, 2020
As the proteoglycan core protein is synthesized and extruded from the Golgi, sugar uridine diphosphate (UDP-sugar) residues are attached by specific enzymes in a specific sequence to the hydroxyl group of a serine residue in the core protein (Figure 4).31a After completion of the linkage region, UDP-glucuronic acid and UDP-galactosmine residues are alternatively attained by two distinct transferases to the nonreducing end of the molecule. Sulfation occurs after incorporation of the sugar residue.
In silico prediction of post-translational modifications in therapeutic antibodies
Published in mAbs, 2022
Tyrosine sulfation is an enzymatic modification that is catalyzed by tyrosylprotein sulfotransferases (TPSTs). During sulfation, a sulfate group is attached to the hydroxyl group of tyrosine residues.111 Tyrosine sulfation has been reported for a few monoclonal and bispecific antibodies.111–114 Sulfation of mAbs can occur in Chinese hamster ovary (CHO) cells during the cell culture. The degree of tyrosine sulfation in CHO cells varies due to differential expression of phosphoadenosine-5ʹ-phosphosulfate (PAPS) synthetase and TPST. PAPS synthetase converts ATP to PAPS; TPST transfers the sulfo group from PAPs to tyrosine residues.115 Sulfation in mAbs generates acidic variants,111 but the impact of tyrosine sulfation on the safety and efficacy of therapeutic antibodies has not yet been established.5
Platelet activation by charged ligands and nanoparticles: platelet glycoprotein receptors as pattern recognition receptors
Published in Platelets, 2021
Samantha J. Montague, Pushpa Patel, Eleyna M. Martin, Alexandre Slater, Lourdes Garcia Quintanilla, Gina Perrella, Caroline Kardeby, Magdolna Nagy, Diego Mezzano, Paula M. Mendes, Steve P. Watson
Human PEAR1 is a novel platelet and endothelial receptor that mediates powerful activation of platelet by sulfated polysaccharides, including fucoidans and dextran-sulfate.59 Sulfation is critical for activation. The site of interaction has been mapped to the thirteenth EGF-like repeat in PEAR1 which contains a cluster of positively charged amino acids in a conserved heparin binding-like consensus sequence. The co-crystallization of PEAR1 with its ligands will map the critical amino acids and potentially provide information on the endogenous ligand. Interestingly, we have shown that in mouse platelets, sulfated glycopolymers mediate activation through CLEC-2 with only a partial role for PEAR159 and speculate that this may be due to the much higher expression of CLEC-2 in mouse platelets compared to humans.88 If this is the case, this illustrates the promiscuity of charged ligands consistent with the charge playing a dominant role in mediating activation.
Recent developments in predicting CYP-independent metabolism
Published in Drug Metabolism Reviews, 2021
Nikhilesh V. Dhuria, Bianka Haro, Amit Kapadia, Khadjia A. Lobo, Bernice Matusow, Mary A. Schleiff, Christina Tantoy, Jasleen K. Sodhi
In general, the sulfation reaction is a detoxification process in which the substrate is metabolized to a more polar water-soluble moiety that can more easily be excreted in the urine, however, SULTs are also involved in the bioactivation of certain compounds that contain allylic alcohols, benzyl alcohols, aromatic hydroxylamines, amino azo dyes, terpenes, and other compounds (Banoglu 2000; Glatt 2000; Gamage et al. 2006; Diao et al. 2014). More recently, pirifenidone has been shown to be bioactivated by CYP enzymes and SULTs resulting in covalent binding to proteins (Zhou et al. 2020). It has been well documented that pirifenidone, a drug that is used to treat idiopathic lung fibrosis, is also associated with idiosyncratic hepatic injury often leading to acute liver failure (Verma et al. 2018), thus these findings provide valuable information for medicinal chemists and drug metabolism scientists toward the future design of safer therapeutics.