China
Africa
Explore chapters and articles related to this topic
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).
Carboxylesterase Inhibitors: Relevance for Pharmaceutical Applications
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Besides the key roles in endo- and xenobiotic metabolism, CES also have other biological roles, such as trafficking and retention of proteins in the ER. In the ER, CES1 and CES2 appear to regulate protein trafficking, including release of proteins. For instance, CES1 can directly bind to the C-reactive protein (CRP) and holds this small protein before its release into the plasma (Yue et al., 1996; Li et al., 2016). CES use a region of amino acid sequence adjacent to the “side door,” which comprises the loop between α15 and β18, to contact CRP. These CES could hold a small reservoir of CRP within the ER, and then release it during the stage of tissue injury. It has also been reported that CES can directly interact with β-glucuronidases, the enzymes responsible for the removal of glucuronic acid moieties which are typically conjugated to drugs and endobiotics by the UDP-glucuronosyltransferase (UGT) enzymes, in the ER (Zhen et al., 1993). Although the interactions between β-glucuronidases with CES have not been extensively investigated, several studies have demonstrated that some compounds (such as organophosphate) are capable of inducing the release of β-glucuronidases from the ER by disrupting the β-glucuronidase-CES1 complex (Zhen et al., 1993).
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
Environmental impact and biological removal processes of pharmaceutically active compounds: The particular case of sulfonamides, anticonvulsants and steroid estrogens
Published in Critical Reviews in Environmental Science and Technology, 2020
Cristiano S. Leal, Daniela P. Mesquita, António Luís Amaral, Almerinda M. Amaral, Eugénio C. Ferreira
The metabolism of CBZ in the human body leads to the formation of 10,11-epoxycarbamazepine (EP-CBZ) and 10,11-dihydro-10,11-trans-dihydroxycarbamazepine (DiOH-CBZ). The CBZ is transformed by the cytochrome P450 3A4 (CYP3A4) in the liver and possibly undergoes glucuronidation by UDP-glucuronosyltransferase-2B7 (UGT2B7) isoenzyme. Only 3% of CBZ remains unchanged when excreted, and is mainly found in the urine, whereas their (mono)hydroxylated and conjugated metabolites can be found in the feces (RxList, 2016a; INCHEM, 2016; Toxnet, 2016).