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General toxicology
Published in Timbrell John, Study Toxicology Through Questions, 2017
(d) The NIH shift is the term used to describe the chemical rearrangement which occurs during the cytochrome P450 mediated oxidation of aromatic compounds. The rearrangement was discovered at and reported by workers from the National Institutes of Health (NIH) in the U.S.A., hence the name. The phenomenon can best be illustrated in the oxidation of naphthalene (see figure page 51). When naphthalene is labelled with a deuterium atom at position 1 , the products of cytochrome P450 mediated oxidation are 1- and 2-naphthols. In both products some deuterium is lost, but in the 1-naphthol product deuterium is found to have moved to the 2 position. In the 2-naphthol, some deuterium is replaced by hydrogen. This indicates that an epoxide intermediate is formed. The ratio of hydrogen to deuterium in the products and the ratio of 1-naphthol to 2-naphthol reflect the isotope effect of deuterium and are consistent with the postulated mechanism as shown in the figure below.
The Study of Drug Metabolism Using Radiotracers
Published in Graham Lappin, Simon Temple, Radiotracers in Drug Development, 2006
The elucidation of NIH shift* products in the metabolism of GW420867X (a reverse transcriptase inhibitor intended as an anti-HIV drug) serves as an example where LC–1H-NMR and 19F-NMR were used to elucidate the structures of the metabolites.20 (The NIH shift is explained in Appendix 1, Table 3.4). In the present example, the NIH shift involved the migration of a fluorine atom on an aromatic ring, as shown in Figure 3.7. The two products could be separated on HPLC, but they had virtually identical mass spectra. The chemical shifts in the 18F-NMR and 1H-NMR spectra allowed unambiguous identification.
LC-MS/MS based detection and characterization of covalent glutathione modifications formed by reactive drug of abuse metabolites
Published in Xenobiotica, 2019
R. Allen Gilliland, Carolina Möller, Anthony P. DeCaprio
Manual metabolite prediction analysis suggested that, in many cases, formation of the adduct is associated with an “NIH shift” pathway. There are several proposed mechanisms by which an NIH shift may occur, however, the prevailing theory, which has been experimentally corroborated, involves formation of an unstable epoxide which then undergoes a hydride shift (Jerina & Daly, 1974; Ortiz de Montellano & Nelson, 2011). While this process is typically followed by a rearomatization step, in situations where GSH or a similar nucleophile is present, rearomatization is not always seen (Guengerich, 2003).