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In Vitro Bioactivation of 3-(N-Phenylamino)propane-1,2-diol by Human and Rat Liver Microsomes and Recombinant P450 Enzymes. Implications for Toxic Oil Syndrome.
|Authors:||Martínez-Cabot, Anna; Morató, Anna; Commandeur, Jan N. M.; Vermeulen, Nico P. E.; Messeguer Peypoch, Ángel|
|Keywords:||Toxic Oil Syndrome|
Rat liver microsomas
|Publisher:||American Chemical Society|
|Citation:||Chemical Research in Toxicology; vol :20, 1218-1224|
|Abstract:||Toxic oil syndrome (TOS) was a massive food-borne intoxication that occurred in Spain in 1981. Epidemiological studies imputed 3-(N-phenylamino)propane-1,2-diol (PAP) derivatives as the toxic agents. The in vitro bioactivation of PAP by rat and human liver microsomes was studied. In both cases, 3-[N- (4′-hydroxyphenyl)amino]propane-1,2-diol (1) was detected as the main metabolite. Inhibition studies with pooled human liver microsomes in the presence and absence of P450-specific inhibitors suggest that 2C8 and 2E1 are the main enzymes involved in PAP bioactivation, followed by 3A4/5, 1A1/2, and 2C9. Incubations of PAP with 10 different recombinant P450 enzymes showed that 2C8, 2C9, 2C18, 2D6, and 2E1 catalyzed PAP 4′-hydroxylation. Incubations of phenol 1 with rat and human liver microsomes in the presence of GSH resulted in the formation of a glutathione conjugate of a quinoneimine metabolite derived from 1. In rat liver microsomes, P450 enzymes play a key role in the bioactivation of 1, whereas in human liver microsomes, autoxidation appears to be the major mechanism. The implications of these results for toxic oil syndrome are discussed.|
|Description:||7 paginas, 3 figuras, 2 esquemas, 2 tablas.|
|Publisher version (URL):||http://dx.doi.org/10.1021/tx700209p|
|Appears in Collections:||(IQAC) Artículos|
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