China
Africa
Explore chapters and articles related to this topic
UGT1A1 Polymorphisms and Mutations Affect Anticancer Drug Therapy
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Tristan M. Sissung, Roberto Barbier, Lisa M. Cordes, William D. Figg
Irinotecan is a prodrug that possesses a dipiperidino side chain linked to the active molecule via a carboxyl-ester. As such, carboxylesterase cleavage through near-ubiquitous carboxylesterase activity (CES1 and CES2) results in the formation of SN-38 (Fig. 12.2) [69]. Irinotecan is also oxidized by the cytochrome P450 (CYP) 3A4 to two metabolites: APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin) and NPC (7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin). Of these, APC is a major oxidative metabolite and is inactive, while NPC can be hydrolyzed by CES to SN-38 [69]. SN-38 itself is further glucuronidated in the liver and intestine to form the inactive SN-38G. SN-38G is then excreted into the small intestine via bile where it can be deconjugated back to SN-38 in the gut and intestine as described above. SN-38 may be re-conjugated to SN-38G after reabsorption into the intestinal tissues [69]. Hepatic uptake of irinotecan and its metabolites is governed by OATP1B1, and hepatobiliary efflux is governed by numerous ATP-binding cassette transporters (Fig. 12.2).
Cholinergic Agonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Rupali Patil, Aman Upaganlawar
Accidental poisoning with many OPs like insecticides can produce a harsh type of demyelination in the peripheral nerve which further causes progressive weakness and loss of sensation. In 1931, contamination of fruit juice with an OP insecticide affected around 20,000 Americans (Brunton, 2011). The correct mechanism of the above reaction is ill understood, but it is considered to be a result from inhibition of an esterase (not ChE itself) precise to myelin. The activities of plasma and liver carboxylesterases (aliesterases) and plasma BuChE are blocked irreversibly by OPs (Lockridge and Masson, 2000); their scavenging capability for OPs can provide partial protection for inhibition of AChE in the nervous system. The carboxylesterases making malathion and other OPs less active or inactive by catalyzing the hydrolysis of carboxyl-ester linkages. Toxicity produced by simultaneous contact of two organophosphorus insecticides can show synergistic effects as carboxylesterases are also inhibited by OPs (Brunton, 2011).
Using a Recombinant Metagenomic Lipase for Enantiomeric Separation of Pharmaceutically Important Drug Intermediates
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Rakesh Kumar, Uttam Chand Banerjee, Jagdeep Kaur
Among biocatalysts, lipases (triacylglycerol acylhydrolases, EC 3.1.1.3) find immense application in industries. They are best defined as carboxylesterases which catalyze both the hydrolysis and synthesis of long-chain acylglycerols (Anthonsen et al., 1995). The catalysis occurs at the lipid–water interface, a phenomenon, termed interfacial activation (Verger, 1997; Schmid et al., 1998). Lipase-catalyzed reactions have received much attention in recent years, as they are increasingly being used in biotechnological applications in the chemical, food, and pharmaceutical industries (Keng et al., 2008; Noel et al., 2003; Weber et al., 2004, 2006).
Analysis of carboxylesterase 2 transcript variants in cynomolgus macaque liver
Published in Xenobiotica, 2019
Yasuhiro Uno, Yoshiyuki Igawa, Maori Tanaka, Kayoko Ohura, Masakiyo Hosokawa, Teruko Imai
Carboxylesterase (CES, E.C. 3.1.1.1), a member of the serine esterase superfamily, is important for hydrolysis of foreign substances containing ester- or amide-bonds, such as cocaine, heroin, 6-monoacetylmorphine, lidocaine and butanilicaine (Alexson et al., 2002; Hosokawa et al., 1987; Hosokawa, 2008). CES is a gene family comprising at least six members, CES1-CES6, in humans (Holmes et al., 2010). Among these members of the CES gene family, CES1 and CES2 are largely responsible for metabolism of drugs, such as angiotensin-converting enzyme inhibitors (e.g. temocapril) and anti-tumor drugs (e.g. irinotecan) (Hosokawa, 2008). In humans, liver and intestine show characteristic patterns of CES expression: the main hepatic and intestinal CESs are CES1 and CES2, respectively. Therefore, CES2 plays a major role in CES-dependent drug metabolism after oral administration in humans (Imai, 2006).
Methoxsalen as an in vitro phenotyping tool in comparison with 1-aminobenzotriazole
Published in Xenobiotica, 2019
Raghava Choudary Palacharla, Parusharamulu Molgara, Hanumanth Rao Panthangi, Rajesh Kumar Boggavarapu, Arun Kumar Manoharan, Ranjith Kumar Ponnamaneni, Devender Reddy Ajjala, Ramakrishna Nirogi
In addition to the P450 enzymes, both ABT and methoxsalen are inhibitors of MAO enzymes with IC90 values falling within the concentrations used for nonspecific P450 inactivation. ABT is not an inhibitor of AO and FMO mediated phthalazine oxidation and benzydamine N-oxidation (IC50 >10,000 µM), respectively. Methoxsalen is an inhibitor of AO mediated phthalazine oxidation with an IC50 value of 382 µM which is slightly higher than the concentration of methoxsalen (300 µM) that can be used as a nonspecific inactivator of P450 enzymes. Methoxsalen and ABT did not show significant inhibition of the metabolism of clopidogrel, the standard substrate for CES1, indicating that both the compounds are not inhibitors of CES1. However, a detailed study is required for further confirmation on the inhibition of other isoforms of carboxylesterase enzymes.
Evaluating mice lacking serum carboxylesterase as a behavioral model for nerve agent intoxication
Published in Toxicology Mechanisms and Methods, 2018
Emily N. Dunn, Teresa M. Ferrara-Bowens, Mark E. Chachich, Cary L. Honnold, Cristin C. Rothwell, Heidi M. Hoard-Fruchey, Catherine A. Lesyna, Erik A. Johnson, Douglas M. Cerasoli, John H. McDonough, C. Linn Cadieux
The increasing threat of terrorist attacks utilizing nerve agents emphasizes the need to develop improved small animal models for development of efficacious medical countermeasures that are applicable to humans (Maxwell et al. 1987; Duysen et al. 2011). Serum carboxylesterase is produced by the Es1 gene (Duysen et al. 2011, 2012). Duysen et al. (2011) created a serum carboxylesterase knockout (Es1 KO) mouse that was found to lack the carboxylesterase enzyme in plasma while maintaining normal carboxylesterase levels in the liver, intestine, lung, and other tissues. Adult male Es1 KO mice and their WT controls were exposed to non-lethal doses of 10 organophosphorus compounds including parathion, a compound known to interact directly with serum carboxylesterase (Karanth and Pope 2000). With parathion exposure, Es1 KO mice exhibited muscle fasciculations, flattened posture, decreased handling reaction, eye lacrimation, and reduced mobility. In control mice exposed to the same dose of this compound, no behavioral toxic signs were observed, demonstrating that serum carboxylesterase plays an important role in protecting the mice from the toxic signs of parathion exposure (Duysen et al. 2012).