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Paediatric clinical pharmacology
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
Sulphation is the other major phase 2 metabolic pathway and results in formation of water soluble metabolites that can be excreted renally [39,40]. Sulfotransferases are the enzymes involved in sulphation. The total number of sulfotransferase enzymes are unknown but are divided into two groups, catechol sulfotransferases and phenol sulfotransferases. The ontogeny of sulphation is different for different drugs. The developmental profiles of glucuronidation and sulphation are illustrated by the examples of morphine and paracetamol, which are markedly different.
Renal Drug-Metabolizing Enzymes in Experimental Animals and Humans
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
The endogenous sulfate pool is limited and may be depleted by extensive sulfate conjugation. Renal tissue contains sulfotransferase activity; in the rabbit kidney the concentration of PAPS and sulfotransferase are higher in the renal cortex and decline through to the medulla (Hjelle et al., 1986). The perfused rat kidney can sulfate various phenols, e.g., 1-naphthol, dimethylaminophenol, and paracetamol (Elbers et al., 1980; Emslie et al., 1981; Redegeld et al., 1988). Likewise, the isolated perfused human kidney and human renal cortical slices can sulfate phenol and 4-nitrophenol (Diamond et al., 1982; Powis et al., 1987). Isolated rat renal cell preparations can also synthesize sulfate conjugates of paracetamol (Jones et al., 1979), 7-hydroxycoumarin (Fry and Perry, 1981; Dawson et al., 1983), and 1-naphthol (Schwenk and Locher, 1985). The renal sulfotransferases are relatively uncharacterized, and important questions that remain to be answered are (1) are there multiple forms of renal sulfotransferase? (2) are they induced by agents that induce UDPGTs and cytochrome(s) P-450? (3) are there marked differences across species in the renal enzyme or its substrate specificity?
Metabolic Activation of Aromatic Amines and Amides and Interactions with Nucleic Acids
Published in Philip L. Grover, Chemical Carcinogens and DNA, 2019
The activation pathway through O-esterification by sulfuric acids seems to be restricted exclusively to liver. DeBaun et al.44 were unable to detect sulfotransferase activity in kidney, mammary gland, and s.c. tissue. Similarly, Irving et al.47 did not detect this enzymic activity in the sebaceous ear duct gland. However, in each of these tissues N-hydroxy-AAF has strong carcinogenic activity so that other activation reactions must be involved in these organs.
2-Naphthalenemethanol participates in metabolic activation of 2-methylnaphthalene
Published in Xenobiotica, 2022
Kunna Li, Ying Zou, Yang Wang, Mengyue Zhou, Jing Li, Rong Tan, Shiyu Zhang, Weiwei Li, Jiang Zheng
The sulfonation reaction is an important phase II conjugative reaction in drug metabolisim (Hui and Liu 2015). The superfamily of sulfotransferases (SULTs) plays an important role in catalysis of the conjugation reactions. The resulting conjugates are highly hydrophilic and readily excreted in urine. A high-energy donor, 3′-adenosine phosphate-5′-phosphosulfuric acid (PAPS), is needed for the conjugative reaction. Specifically, SULTs catalyse the transfer of sulphate to amino, hydroxyl, or N-oxide groups (Nowell and Falany 2006; Kurogi et al. 2021). 2-NM contains a benzylic hydroxyl group, and many drugs with benzyl alcohol structure can undergo a sulfonation reaction under the catalysis of SULTs (Li et al. 2019). Such conjugates have potentials to induce toxicities, since benzylic sulphates are known electrophilic species reactive to biomolecules (James 2014). The resulting modification of biomolecules could induce a variety of toxicities. For example, aloe-emodin was metabolised to the corresponding sulphate. The formation of such metabolite was found to be partially responsible for the cytotoxicity of aloe-emodin (Zhou et al. 2020).
Predictive role of polymorphic variants of phase II drug metabolising enzyme in modulating toxicity in North Indian lung cancer patients undergoing chemotherapy
Published in Xenobiotica, 2022
Harleen Walia, Parul Sharma, Navneet Singh, Siddharth Sharma
Mechanistically, in order to understand the cisplatin induced kidney damage, few studies have reported cisplatin's role at cellular level in mediating kidney damage. The accumulation of cisplatin occurs in the proximal tubular epithelial cells of the renal region, and the organic cation transporter 2 plays an essential role in mediating the uptake of cisplatin, thus, causing nephrotoxicity. Factors like oxidative stress, inflammatory responses, DNA damage are involved in the mechanism of cisplatin-induced nephrotoxicity (Miller et al. 2010). It has also been reported that indoxyl sulphate (IS), a sulphate conjugated uraemic toxin,is involved in cisplatin-induced nephrotoxicity in animal models. Indoxyl sulphate is produced in the liver by the oxidation of indole mediated through the CYP2E1 and CYP2A6 oxidation process, followed by the sulfonation of indoxyl by sulfotransferases (Banoglu and King 2002). A study has shown that SULT1A1 is responsible for the sulfonation activity of indoxy. Thus, we propose that individuals carrying both the alleles for wild-type genotype have higher catalytic activity for the SULTI1A1 enzyme, therefore increasing the sulfonation of indoxyl. This might lead to the accumulation of IS in the renal tubules and thus inducing nephrotoxicity (Iwata et al. 2007; Yabuuchi et al. 2021). Our study observed that individuals carrying the mutant alleles had lower odds of developing nephrotoxicity as the sulfotransferase enzyme in such subjects has less enzyme activity, thus leading to less sulfonation of indoxyl and leading to less nephrotoxicity.
Genetic polymorphism of Arg213His variant in the SULT1A1 gene is associated with reduced susceptibility to lung cancer in North Indian population
Published in Xenobiotica, 2021
Harleen Kaur Walia, Navneet Singh, Siddharth Sharma
The human sulfotransferases (SULTs) is an important phase II detoxification enzyme that catalyses the sulphonate conjugation of various endogenous compounds such as neurotransmitters, many drugs, steroid and thyroid hormones, xenobiotics and pro-carcinogenic agents (Xiao et al. 2014; Dash et al. 2019). The sulfotransferases are found to be differentially expressed in different types of human tissues such as the lung, brain, colon, liver, platelet as well as other sites (Jones et al. 1992; Li et al. 2008). Sulfonation is commonly known to be a detoxifying mechanism that produces more water-soluble and therefore fewer toxic metabolites; however, this conjugation reaction of some compounds creates electrophiles that may bind to DNA to form carcinogen-DNA adducts (Coughtrie et al. 1998; Banoglu, 2000). So far, 13 human cytosolic SULT isoforms have been recognized and further grouped as four key families: SULT1, SULT2, SULT4, SULT6 (Blanchard et al. 2004; Kumar et al. 2013). The most expressed member of the phenol SULT1 family is SULT1A1. The SULT1A1 enzyme is expressed by the SULT1A1 gene, which maps to chromosome 16p11.2-p12.1. Apart from the inactivation of toxic compounds SULT1A1 isoform is also involved in the bioactivation of procarcinogens such as polycyclic aromatic hydrocarbons (PAHs) and heterocyclic amines (HCAs), both of which are present in tobacco smoke (Bardakci et al. 2008; Koike et al. 2008; Kumar et al. 2013).