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Role of Metabolism in Chemically Induced Nephrotoxicity
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Although the liver has generally been the focus of most drug metabolism studies and has been viewed as being quantitatively the most important site of metabolism in the body, numerous studies over the last 2 decades have shown that the kidneys are capable of carrying out extensive oxidative, reductive, hydrolytic, and conjugation processes (Anders, 1980; Jones et al., 1980). Enzyme systems similar to those responsible for these processes in extrarenal tissues are involved in renal drug metabolism. Examples include cytochrome P-450 with its associated NADPH-dependent reductase, the flavin-containing monooxygenase, alcohol and aldehyde dehydrogenases, epoxide hydrolase, esterases, acetylases, and the conjugation enzymes, including glucuronosyltransferases, sulfotransferases, and glutathione (GSH) S-transferases. Moreover, the kidneys are critical sites for biotransformation of many classes of xenobiotics, because certain metabolic pathways that are present at low activities in other tissues are present at high activities in specific regions of the nephron. One of the best examples of this type of drug metabolism pathway is the mercapturic acid pathway.
Pregnancy-Related Proteins Detected by Their Biological Activities
Published in Gábor N. Than, Hans Bohn, Dénes G. Szabó, Advances in Pregnancy-Related Protein Research, 2020
Glutathione S-transferase acts as a detoxicating enzyme for electrophilic compounds. It promotes the first step in the synthesis of mercapturic acid by catalyzing the conjugation of glutathione with several electrophilic compounds.101 Its activity is very high in early placentas. γ-Glutamyl transpeptidase, which catalyzes the second step in the biosynthesis of mercapturic acid by metabolizing glutathione conjugates formed by glutathione S-transferase, reaches its peak in specific activity by the 8th week of pregnancy. The absence of these enzymes from amniotic fluid and their highest activity during early pregnancy seem to indicate a protective mechanism for the fetus during its organogenesis phase when it is at its most vulnerable.66
Acetaminophen, Salicylates, and Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
Acetaminophen is rapidly absorbed from the gastrointestinal tract and uniformly distributed, with peak plasma levels achieved by 0.5 to 2.0 h. Hepatic glucuronide and sulfate conjugation (Reactions 1 and 2, Figure 18.1) produce the inactive corresponding conjugates, which account for 95% of metabolism and elimination in urine. In addition, at therapeutic acute doses, the remaining 4 to 5% of the product is detoxified and eliminated in the minor cytochrome P450 oxidase pathway (Reaction 3). The result is the production of the reactive intermediate, N-acetyl-p-benzoquinoneimine (NAPQI) metabolite. Further conjugation by cellular glutathione results in the production of mercapturic acid and cysteine conjugates (Reaction 4). With chronic use or with large doses,* the glucuronide and sulfate conjugation metabolic routes (1 and 2) are saturated, and more importantly, glutathione stores are depleted (4). This leaves the cytochrome P450 oxidase pathway (Reaction 3) to accumulate the toxic NAPQI metabolite. The binding of NAPQI to hepatocyte membranes and sulfhydryl proteins accounts for the hepatotoxic sequelae.
Artemisia herba-alba aqueous extract improves insulin sensitivity and hepatic steatosis in rodent model of fructose-induced metabolic syndrome
Published in Archives of Physiology and Biochemistry, 2021
Yassine Réggami, Abderrahim Benkhaled, Amel Boudjelal, Hajira Berredjem, Amani Amamra, Halima Benyettou, Nadia Larabi, Abderrahmane Senator, Laura Siracusa, Giuseppe Ruberto
Glutathione S-transferase (GST; E.C.2.5.1.18) catalyzes the conjugation reaction with glutathione in the first step of mercapturic acid synthesis. The enzymatic activity of GST was estimated according to the method of Habig et al. (1974) using 1- chloro-2,4-dinitrobenzene (CDNB) as substrate. In brief, the reaction mixture (3 ml) contained 1 ml of phosphate buffer (100 mM, pH 6.5), 0.1 ml of CDNB (30 mM), 1.7 ml of distilled water and 0.1 ml of liver homogenate. After incubation at 37 °C for 5 min, 0.1 ml of GSH (30 mM) was added to initiate the reaction. Then, the absorbance was monitored for 5 min at 340 nm. The GST activity was reported as nmol of GSH–CDNB conjugate formed min−1 mg−1 protein using molar extinction coefficient of 9.6 mM−1 cm−1.
Hepatoprotective effect of Pandanus odoratissimus seed extracts on paracetamol-induced rats
Published in Pharmaceutical Biology, 2021
Ernawati Sinaga, Ami Fitrayadi, Asrori Asrori, Sri Endarti Rahayu, Suprihatin Suprihatin, Vivitri Dewi Prasasty
About 25% of paracetamol is bound to plasma proteins and partly metabolized by liver microsome enzymes. Paracetamol can be conjugated with glucuronic acid in the liver. At therapeutic doses, 5–15% of paracetamol will be converted by cytochrome P450 to a highly reactive metabolite, N-acetyl-p-benzoquinonymin (NAPQI). NAPQI will be quickly detoxified by conjugation with cell glutathione (Ohba et al. 2016). This reaction results in the formation of cysteine and mercapturic acid excreted in the urine. At the time of paracetamol intoxication, the amount and speed of NAPQI formation exceed the ability of the liver to replenish glutathione reserves. Glutathione depletion causes NAPQI to bind covalently to the cysteine group in proteins. The main target is the mitochondrial protein, which results in damage to ATP production. Mitochondrial dysfunction will also produce reactive oxygen species (ROS) and reactive nitrogen species (RNS), which results in oxidative stresses. These oxidative stresses cause hepatotoxicity (Moyer et al. 2011; Yoon et al. 2016; Tsai et al. 2018).
Mass balance and metabolism of Z-215, a novel proton pump inhibitor, in healthy volunteers
Published in Xenobiotica, 2018
Ryoko Toda, Tomoharu Miyagawa, Yuka Masuda, Yusuke Hoshino, Kazuyoshi Yoshii, Masamichi Hirayama, Minaka Shibuya, Yoshihiro Kawabata
The primary metabolite in human urine (15.5% of dose) was the mercapturic acid conjugate benzimidazole (mH09). The same metabolite was detected in human mass balance studies of other PPIs (Grabowski & Lee, 2012; Setoyama et al., 2006). Furthermore, mH07, which we estimated to be a cysteine conjugate on the benzimidazole ring of Z-215, was detected in small amounts in human urine (Figure 3, Table 5). The mercapturic acid conjugate can be produced via the cysteine conjugate by the enzymatic conversion of glutathione (Commandeur et al., 1995). In fasted male mice, single oral administration of Z-215 produced a glutathione conjugate on the benzimidazole ring of Z-215, which was excreted in bile but not in urine or faeces. Further, the mercapturic acid conjugate on the benzimidazole ring of Z-215 was detected in plasma and urine (data on file). Therefore, our finding suggests that a glutathione conjugate on the benzimidazole ring of Z-215, which was ND in human excreta and plasma in this study, may also be formed in humans.