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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.

AuthorsMartínez-Cabot, Anna; Morató, Anna; Commandeur, Jan N. M.; Vermeulen, Nico P. E.; Messeguer Peypoch, Ángel
KeywordsToxic Oil Syndrome
P450 Enzymes
3-(N-Phenylamino) propane-1,2-diol
Rat liver microsomas
Issue Date8-Mar-2007
PublisherAmerican Chemical Society
CitationChemical Research in Toxicology; vol :20, 1218-1224
AbstractToxic 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.
Description7 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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