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Toxicological Chemistry
Published in Stanley E. Manahan, Environmental Chemistry, 2022
A Phase II reaction occurs when an endogenous species is attached by enzyme action to a polar functional group that often, though not always, is the result of a Phase I reaction on a xenobiotic species. Phase II reactions are called conjugation reactions in which enzymes attach conjugating agents to xenobiotics, their Phase I reaction products, and nonxenobiotic compounds (Figure 22.7). The conjugation product of such a reaction is usually less toxic than the original xenobiotic compound, less lipid-soluble, more water-soluble, and more readily eliminated from the body. The major conjugating agents and the enzymes that catalyze their Phase II reactions are glucuronide (UDP glucuronosyltransferase enzyme), glutathione (glutathione S-transferase enzyme), sulfate (sulfotransferase enzyme), acetyl (acetylation by arylamine N-acetyltransferase enzymes), and methyl groups (methyltransferases).4 The most abundant conjugation products are glucuronides. A glucuronide conjugate is illustrated in Figure 22.8, where –X–R represents a xenobiotic species conjugated to glucuronide and R is an organic moiety. For example, if the xenobiotic compound conjugated is phenol, HXR is HOC6H5, X is the O atom, and R represents the phenyl group –C6H5.
HIV-Integrase
Published in Mihai V. Putz, New Frontiers in Nanochemistry, 2020
Corina Duda-Seiman, Daniel Duda-Seiman, Mihai V. Putz
Pharmacokinetics of HIV-integrase inhibitors is a very interesting issue; its understanding of providing information regarding the route of administration, dose, and efficiency. Glucuronidation is the main metabolic pathway of RAL, obtaining RAL glucuronide (RAL-GLU) via UDP-glucuronosyltransferase 1A1 (UGT1A1). RAL and RAL-GLU can be simultaneously detected and quantified using liquid chromatography-tandem mass spectrometry. This method provides knowledge about the therapeutic window of RAL in different patient categories. (Wang et al., 2011). RAL is rapidly absorbed from the gastrointestinal tract when orally administered; peak plasma concentrations are achieved after 0.5–1.3 hours. 9% of the administered dose is excreted unmodified in urine. (Gupta et al., 2015). Recently, a liquid chromatography-tandem mass spectrometry assay was proven to be sufficiently sensitive and accurate to quantify antiretroviral drugs including RAL in plasma and saliva, providing the relationship between drug concentrations in plasma and saliva. (Yamada et al., 2015).
Ecotoxicological Effects of Process Changes Implemented in a Pulp and Paper Mill: A Nordic Case Study
Published in Mark R. Servos, Kelly R. Munkittrick, John H. Carey, Glen J. Van Der Kraak, and PAPER MILL EFFLUENTS, 2020
Microsomal and cytosolic fractions were separated from homogenized liver by ultracentrifugation. Ethoxyresorufin-o-deethylase (EROD), uridine-5′-diphosphate glucuronosyltransferase (UDP-GT, substrate: p-nitrophenol) and glutathione-S-transferase (GST, substrate: 1-chloro-2,4-dinitrobenzene) activities were determined (Lindström-Seppä and Oikari 1989). In order to yield enough tissue material for analysis, liver samples from two to four fish were combined in 1991 (3–5 assays from 10–14 fish per site); individual animals were analyzed in 1993 (14–18 fish per site). Concentration of immunoglobulin M (IgM) in whitefish plasma was measured by enzyme-linked immunosorbent assay (Aaltonen et al. 1994). Antibodies against chromatographically purified plasma IgM of trout (Salmo trutta L.) and whitefish in 1991 and 1993, respectively, were raised in rabbits and used as the trapping and detecting agents, applying the double antibody sandwich method. For both species, the cross-reactivity with whitefish IgM was strong. Plasma lactate dehydrogenase (LDH) and aspartate aminotransferase (ASAT) activities in 1991 and 1993, respectively, were assayed using Boehringer diagnostic kits (191353, 191337).
The toxic contaminants of Aspalathus linearis plant material as well as herb–drug interactions may constitute the health risk factors in daily rooibos tea consumers
Published in International Journal of Environmental Health Research, 2023
Moreover, other metabolizing enzymes may be involved. Marnewick et al. (2003) reported that unoxidized rooibos potentiates in rats the activity of the hepatic second phase enzymes (UDP-glucuronosyltransferase and glutathione-S-transferase) that play a role in glucuronidation reactions transforming lipophilic drugs into more polar metabolites as well as catalyze the conjugation of reduced glutathione to electrophilic substrates. Abrahams et al. (2019) showed that aspalathin-enriched ‘unfermented’ extract also modulated the expression of some genes encoding polyphenol-metabolizing enzymes. In the rat liver, the upregulation of the genes of aldehyde dehydrogenase, glucose phosphate isomerase and cytochrome P450 as well as downregulation of 17β-hydroxysteroid dehydrogenase type 2 were observed, whereas in the culture of primary hepatocytes only aspalathin itself provoked similar CYP and 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) changes. These interactions suggest, e.g. improved alcohol metabolism and interaction with steroid hormones, resulting in the smaller breakdown of estradiol, testosterone and 5α-DHT in the liver as well as enhanced estrogen production. Besides Schloms et al. (2014) reported glucocorticoid synthesis and metabolism affected by rooibos extract in the mechanism of the 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) inhibition, resulting in a decreased cortisol:cortisone ratio. The interference of rooibos tea with hepatic metabolism based on available research is gathered in Figure 3.
Association between polychlorinated biphenyl exposure and thyroid hormones: a systematic review and meta-analysis
Published in Journal of Environmental Science and Health, Part C, 2022
Christine C. Little, Joshua Barlow, Mathilda Alsen, Maaike van Gerwen
In addition to effects mediated by structural homology, PCBs are known to disrupt metabolism of thyroid hormones through alterations in the enzymatic processes of deiodination and glucuronidation. PCBs have been shown to upregulate T4 glucuronidation via induction of hepatic UDP-glucuronosyltransferase in rat models, thereby reducing levels of circulating T4.7,44 Additionally, PCBs may impact thyroid homeostasis by disrupting extrathyroidal conversion of T4 to T3. Conversion of T4 to its biologically active form T3 is tightly controlled by three types of deiodinases in human metabolism. Type-I and type-II deiodinases catalyze the removal of iodine residues from the outer ring of T4 to form T3, whereas type-III deiodinase catalyzes the removal of iodine from the inner ring of T4 or T3 to form the biologically inactive hormone reverse T3 (rT3).45 PCBs have been demonstrated to decrease activity of type-I and type-II deiodinases,7,45,46 while increasing activity of type-III deiodinase,47 though it is important to note that many of these effects appear to be tissue-dependent and vary between studies. Thus, PCB exposure may decrease circulating levels of T3 by impairing conversion of T4 into T3 and by promoting inactivation of T3 into rT3. In addition, PCBs have been shown to alter male and female reproductive hormones due to their estrogen-like structure.48–50 Reproductive hormones are known to directly influence thyroid hormone levels through regulation of the transport protein thyroxine binding globulin, providing an indirect pathway through which PCBs may disrupt thyroid hormone homeostasis.51–53
Erythromycin in the aquatic environment: deleterious effects on the initial development of zebrafish
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Valeska Toffolo Minski, Cristiane Garbinato, Nathana Thiel, Anna Maria Siebel
Liu et al. (2014) demonstrated that in crucian carp exposed to erythromycin at 4, 20, or 100 μg/L for 28-d accumulation of antibiotic was noted in muscle, gills, and liver accompanied by enzymatic changes. In the brain, a decrease was observed in the acetylcholinesterase (AChE) activity. In the liver, an increase was found in the activities of the enzymes 7-ethoxyresorufin O-deethylase (EROD) and superoxide dismutase (SOD). Previously Rodrigues et al. (2019) investigated the effects of acute (96 hr) and chronic (28 d) exposure to erythromycin in rainbow trout,Oncorhynchus mykiss. The analyzed biomarkers for different endpoints included: detoxification (EROD) glutathione S-transferases (GST), and uridine-diphosphate-glucuronosyltransferases, energy production (lactate dehydrogenase, LDH), and neurotransmission (AChE). Acute (ranging from 0.001 to 10 mg/L erythromycin) and chronic (ranging from 0.05 to 0.8 μg/L erythromycin) exposures increased hepatic EROD activity. Chronic treatment elevated GST activities in gills and reduced the branchial uridine-diphosphate-glucuronosyltransferase activities. No marked changes were noted in LDH lactate and AChE activities. Evidence indicated that erythromycin-induced alterations in the detoxification system in rainbow trout (Rodrigues et al. 2019). Treatment with different concentrations of erythromycin (ranging from 2 µg/L to 2 mg/L) for 96 hr decreased the burst speed and swimming speed in zebrafish (Danio rerio) and medaka (Oryzias latipes) (Li and Zhang 2020). Further, exposure to erythromycin reduced the expression of genes associated with energy metabolism in fish muscles. Finally, antibiotic-treated medaka showed disruption in the transcription of phototransduction genes, and in zebrafish endocrine disruption was noted (Li and Zhang 2020).