China
Africa
Explore chapters and articles related to this topic
Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Both P450 and glutathione transferase play a role in the bioactivation of dihaloalkanes. The major pathway for 1,2-dichloroethane involves glutathione transferase conjugation and subsequent formation of electrophilic episulfonium derivatives. In addition, P450-mediated carbon-halogen oxidation and halogen oxidation play a role in bioactivation. Carbon-halogen oxidation results in an unstable gem-chlorohydrin intermediate that nonenzymatically dehydrohalogenates to form the electrophile, 2-chloroacetaldehyde. Halogen oxidation by P450 yields l-chloroso-2-chloroethane, which is electrophilic. This product nonenzymatically forms additional electrophiles. Alternatively, it may be conjugated by glutathione transferases, with ultimate formation of the episulfonium electrophile. Additional, but minor, microsomal bioactivation pathways include initial carbon-halogen reduction and dehydrohalogenation to electrophilic species.
Reproductive System and Mammary Gland
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Justin D. Vidal, Charles E. Wood, Karyn Colman, Katharine M. Whitney, Dianne M. Creasy
Endometrial adenomas or adenocarcinomas are generally rare tumors in most standard strains and species used in nonclinical toxicology testing. Exceptions include the Han-Wistar rat and the rabbit, which can have high background incidences of endometrial carcinomas (Deerberg et al. 1981; Elsinghorst et al. 1984). In Wistar rats, these tumors can be induced by chronic disruption of the HPG axis, leading to decreased prolactin, corpus luteum function, and progesterone; reduced antagonism of estrogenic effects in the uterus by progesterone; and increased endometrial gland hyperplasia and tumors (Harleman et al. 2012). This mechanism is generally considered to have low human relevance given that prolactin does not have a key luteotropic role in the normal human ovarian cycle. In mice, endometrial tumors have been induced by a number of xenobiotics including estrogens, bromoethane, chloroethane, and ethylene oxide, administered either chronically, or during critical windows of development (Highman et al. 1978; Newbold et al. 1990, 2001; Picut et al. 2003). Perinatal estrogen exposure may induce neoplasia via a combination of estrous cycle disruption with luteal dysfunction and altered patterns of uterine epithelial differentiation (Kurita 2011; Suen et al. 2016). In macaques, endometrial adenocarcinomas are exceedingly rare; only a few cases have been reported either as spontaneous or treatment-related lesions (Cline et al. 2008).
Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Yuanying Fang, Shaokun Zhang, Min Li, Lijuan Xiong, Liangxing Tu, Saisai Xie, Yi Jin, Yanhua Liu, Zunhua Yang, Ronghua Liu
To a solution of compound 8 (0.4 g, 1.4 mmol) in DMF (10 ml), 1-bromo-2-chloroethane (0.62 g, 4.3 mmol) and K2CO3 (0.6 g, 4.3 mmol) were added. The reaction was stirred at 40 °C for overnight. Then the mixture was poured into ice water. The mix solution was extracted with ethyl acetate for two times, washed with brine for two times. The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography (petroleum ether: EtOAc = 2: 1) to afford the desired product as a claybank solid (0.68 g, 55%). 1H-NMR (600 MHz, CDCl3) δ (ppm): 8.04 (s, 1H), 8.35 (s, 1H), 7.73–7.44 (m, 3H), 4.51 (t, J = 4.4 Hz, 2H), 3.95 (t, J = 4.3 Hz, 2H). MS-ESI: [M + H]+: 291.5.
Design, synthesis and biological evaluation of novel 4-anlinoquinazoline derivatives as EGFR inhibitors with the potential to inhibit the gefitinib-resistant nonsmall cell lung cancers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Caolin Wang, Shan Xu, Liang Peng, Bingliang Zhang, Hong Zhang, Yingying Hu, Pengwu Zheng, Wufu Zhu
Reagents and conditions: (a) acetonitriles, anhydrous, K2CO3, 1-bromo-2-chloroethane or 1-bromo-2-chloropropane, 1 h, rt; (b) DMF, microwave, Small molecule amines, 1 h, rt. (c) triethyl orthoformate, ammonium chloride, r.t.; (d) 1, methanol water, sodium borohydride; 2, diluted hydrochloric acid, heated. 3, hydrogen chloride in methanol, T = 0–20 °C.