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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
CYP2D6 is involved in the metabolism of diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea), a widely used herbicide and antifouling biocide (Figure 3.115) (Abass et al. 2007). Diuron has been classified as a slightly hazardous (toxicity class III) pesticide by World Health Organization. Diuron has been characterized as a “known/likely” human carcinogen by the US Environmental Protection Agency based on the data that diuron induces urinary bladder carcinoma in both sexes of the Wistar rat, kidney carcinoma in the male rat, and breast carcinoma in female NMRI mice. In human liver microsomes, only N-demethylated diuron is formed. Recombinant CYP1A1, 1A2, 2C19, and 2D6 catalyze the N-demethylation of diuron with high activities. Relative contributions of human CYP1A2, 2C19, and 3A4 to hepatic diuron N-demethylation are estimated to be ~60%, 14%, and 13%, respectively. In studies of rats and dogs, N-(3,4-dichlorophenyl)urea is the predominant metabolite in the urine. Small amounts of N-(3,4-dichlorophenyl)-N-methylurea, 3,4-dichloroaniline, 3,4-dichlorophenol, and unchanged diuron are also detected (Hodge et al. 1967). In a hospitalized patient, diuron is completely metabolized, mainly via demethylation and didemethylation with the corresponding metabolites detected in the blood and urine. In addition, high levels of hydroxyphenyldi-uron and moderate levels of 3,4-dichloroaniline are detected in the urine (Van Boven et al. 1990). In a human postmortem case, diuron and its demethylated, didemethylated, and hydroxylated metabolites are all identified in plasma and urine. Diuron levels are as high as 5 mg/l in plasma and 3 mg/l in urine and the total concentration of diuron plus metabolites in plasma is approximately 100 mg/l, with an estimated ingestion of at least several grams (Verheij et al. 1989). In the postmortem case, N-demethyldiuron is the major metabolite, whereas in the hospitalized case, N-didemethyldiuron is the primary metabolite in blood and N-demethyldiuron is dominant in urine.
Molecular signatures associated with diuron exposure on rat urothelial mitochondria
Published in Toxicology Mechanisms and Methods, 2022
Thania Rios Rossi Lima, Estela de Oliveira Lima, Jeany Delafiori, Rodrigo Ramos Catharino, João Lauro Viana de Camargo, Lílian Cristina Pereira
Diuron, 3-(3,4-dichlorophenyl) 1,1-dimethylurea, is a worldwide used herbicide whose biodegradation in the environment or metabolization in mammals results in the metabolites 3-(3,4-dichlorophenyl)-1-methylurea (DCPMU), 3,4-dichlorophenylurea (DCPU) and 3,4-dichloroaniline (DCA) (Giacomazzi and Cochet 2004; APVMA 2011). Since in mammals the excretion of these compounds occurs mainly through urine, the urothelial tissue which lines the urinary tract from the renal pelvis and ureters to the bladder, is one of the most affected by their potential toxicity. Previous studies with diuron demonstrated that its MoA on the urinary bladder of Wistar rats involves chemical metabolic activation leading to initial cytotoxicity followed by cell degeneration, exfoliation and necrosis, continuous regenerative hyperplasia and eventual tumors after a long-term exposure (Nascimento et al. 2006; da Rocha et al. 2010; Ferrucio et al. 2010; Ihlaseh-Catalano et al. 2011; da Rocha et al. 2012; Cardoso et al. 2013; da Rocha et al. 2013; da Rocha et al. 2014; Ihlaseh-Catalano et al. 2014; Fava et al. 2015). Recently, the hypothesis was put forward that this sequence of successive events induced by diuron and/or its metabolites could comprise an Adverse Outcome Pathway (AOP) in which the mitochondrial toxic damage represents the initiating molecular event (MIE) (Souza et al. 2020).
Fluorescent melamine-formaldehyde/polyamine coatings for microcapsules enabling their tracking in composites
Published in Journal of Microencapsulation, 2022
Christian Neumann, Sophia Rosencrantz, Andreas Schmohl, Latnikova Alexandra
PMMA microcapsules loaded with diuron were synthesised through a solvent evaporation process using chloroform as the volatile. The diuron was first dispersed as a solid in the organic phase consisting of PMMA and chloroform, which was then added to the aqueous phase. The chloroform was evaporated at 50–60 °C, so that solid PMMA microcapsules were formed. It can be clearly observed in optical microscopy (Figure 7(A)) that diuron was encapsulated in its solid form inside the transparent PMMA polymer. The diuron microcapsules exhibit a spherical shape with a mean diameter (D50) of 36 ± 11 µm, determined by laser diffraction. The distribution of capsules is monomodal with a SPAN value ((D90 – D10)/D50) of 0.8. Investigation of capsules by FTIR confirms the successful encapsulation of diuron inside the PMMA microcapsules by the appearance of N–H vibration at 3283 cm−1 and the aromatic stretching at 1586 cm−1 and 1522 cm−1 (Figure 7(E)).
Preparation and evaluation of polyphenol derivatives as potent antifouling agents: addition of a side chain affects the biological activity of polyphenols
Published in Biofouling, 2022
Xuan Wang, Xiaohui Jiang, Liangmin Yu
Many heavy metals, such as copper, lead, and arsenic, were widely favoured in early studies because of their effective protective properties in AF coatings. More recently, Irgarol 1051, dichlofluanid, and diuron were used instead. Nevertheless, their high toxicity, which cannot be ignored, is detrimental to human health and the environment (Omae 2003; Li et al. 2013; Ansanelli et al. 2017; Moon et al. 2019; Zhang et al. 2019). Therefore, the research and development of natural green AF agents should be extended further. To satisfy the increasing needs for such AF agents, much research has been carried out, resulting in some notable achievements. Various natural AF agents, such as capsaicin-inspired thiol-ene terpolymer networks, indole derivatives, and capsaicin derivatives, have been proposed for potential use in AF coatings. Natural AF agents, which exhibit low toxicity, broad-spectrum applicability, and biodegradable AF activity, have been proven to be efficient and environmentally friendly (Qian et al. 2015; Feng et al. 2018, 2019).