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Involvement of Dopamine with Various Cancers
Published in Nira Ben-Jonathan, Dopamine, 2020
All five DAR subtypes were expressed in HepG2 cells, an immortalized human liver carcinoma cell line [58]. Cell treatment with the D1R agonists SKF82958 or SKF38393 increased D1R expression and stimulated SULT2A1 sulfotransferase activity. These effects were partially blocked by co-treatment with the specific D1R antagonist SCH23390. These data suggest that D1R is involved in metabolism of drugs and xenobiotics through up-regulation of SULT2A1. 3,3′,4′,7-Tetrahydroxyflavone (fisetin) is an abundant flavonoid that is produced in some vegetables and fruits. It has a similar structure to DA and appears to mimic DA action [59]. Both fisetin and bromocriptine, albeit at high micromolar doses, suppressed the proliferation, migration, and invasion of liver cancer cells. Growth of orthotopically implanted liver cancer xenografts was inhibited by fisetin administration, which was accompanied by higher levels of serum and tumor DA and increased survival rate of the mice [59]. The authors concluded that DA represents a novel therapeutic strategy for suppressing liver cancer progression.
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Veratramine, a steroidal alkaloid originating from Veratrum nigrum, has shown distinct antitumor and antihypertension effects. Unlike most alkaloids, the major reactive sites of veratramine are on rings A and B instead of on the amine moiety. CYP2D6 is the major enzyme mediating hydroxylation of veratramine (Lyu et al. 2015). SULT2A1 conjugates veratramine.
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
Sulfotransferases are conjugative Phase II enzymes that transfer an SO3- group from the cofactor 3′-phosphoadenosine-5′-phosphosulfate (PAPS) to a nucleophilic substrate moiety, such as an alcohol, amine or hydroxylamine (Gamage et al. 2006; Coughtrie 2016). Membrane bound SULTs (located subcellularly in the Golgi apparatus) are responsible for the sulfonation of peptides and proteins, while the cytosolic SULTs are involved in the metabolism of xenobiotics and endogenous compound such as bile acids, neurotransmitters and steroids (Gamage et al. 2006). In humans, cytosolic SULTs are expressed mainly in the liver and small intestine, with lesser degree of expression in the kidney and lung (Riches et al. 2009). There are five major human SULT isoforms (SULT1A1, SULT1B1, SULT1E1, SULT2A1 and SULT1A3), and SULT1A1 is the major isoform in the liver, while SULT1B1 is the major isoform in the small intestine (Riches et al. 2009). Based on a recent quantitative proteomic investigation, it has been reported that SULT abundance can change with age for SULT1A1, SULT1B1 and SULT2A1, whereas SULT1A3 expression was age-independent across 0 to 70 years (Ladumor et al. 2019).
The role of xenobiotic-metabolizing enzymes in the placenta: a growing research field
Published in Expert Review of Clinical Pharmacology, 2020
Ricardo Blanco-Castañeda, Carlos Galaviz-Hernández, Paula C. S. Souto, Victor Vitorino Lima, Fernanda R. Giachini, Carlos Escudero, Alicia E Damiano, L. Jazel Barragán-Zúñiga, Gerardo Martínez-Aguilar, Martha Sosa-Macías
SULTs conjugate sulfate groups to certain compounds (steroids, catecholamines) using 3′-phosphoadenosine 5′-phosphosulfate (PAPS) as a cofactor. In human, four gene families have been identified: SULT1, SULT2, SULT4, and SULT6, but only the first two express in the placenta, encoding for more than one protein each [85]. SULT enzymes are involved in the synthesis and metabolism of steroid hormones, and it is thought that they represent one of the main lines of defense against xenobiotics in the placenta [86]. Substantial SULT activity toward 4-nitro-phenol (SULT1A1) and dopamine (SULT1A3) has been detected in the cytosol of cells from cotyledons, with significant activity throughout the pregnancy starting from the first trimester [57]. SULT1E1 activity toward 17α-ethynylestradiol has also been found in placental-cell cytosol in considerably lower amounts relative to SULT1A1 and SULT1A3 activities [57]. Dehydroepiandrosterone sulfotransferase activity, indicative of SULT2A1 expression, was also present in the placenta, particularly the cotyledon [57]. In the same study, isoforms SULT1A1 and −1A3 were detected in the cytosol of syncytiotrophoblasts, while the expression of SULT1B1 and −1C2 was essentially undetectable. By contrast, SULT2B1b mRNA and protein expression and activity have been uncovered in the nuclei of placental syncytiotrophoblasts at term [58]. Evidence for SULT1A1, −1A3, −1B1, −1E1, and −2B1 mRNA expression in the placenta at term has also been demonstrated [53].
Alterations of drug-metabolizing enzymes and transporters under diabetic conditions: what is the potential clinical significance?
Published in Drug Metabolism Reviews, 2018
Feng Chen, De-Yi Li, Bo Zhang, Jie-Yu Sun, Fang Sun, Xing Ji, Jin-Chun Qiu, Robert B. Parker, S. Casey Laizure, Jing Xu
In human donors, compared with the non-fatty, non-diseased liver samples, the sulfonation activity of the SULT1A1, –1A3 and –1E1 was reduced in the diabetes cirrhosis liver samples, but the SULT2A1 was unchanged (Yalcin et al. 2013). The hepatic mRNA expression of SULT1A1 and –1C1 in SI rats was induced and suppressed, respectively, whereas the SULT1B1 and –1E1 had no significant alterations (Liu et al. 2012).In an HFD-induced diabetic mice model, the SULT2A1 and –1A1 protein expression in the liver was decreased and unchanged, respectively, but the total SULT activity was decreased (Koide et al. 2011). In ob/ob mice, the SULT2A1 and –2A2 mRNA expression in the liver was increased in female rodents, but the counterpart had no obvious changes (Cheng et al. 2008). In human donors, compared with the non-fatty, non-diseased liver samples, the sulfonation activity of the SULT1A1, -1A3 and -1E1 was reduced in the diabetes cirrhosis liver samples, but the SULT2A1 was unchanged (Yalcin et al. 2013).