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.
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.
Department of Biological Organic Chemistry, IIQAB, Consejo Superior de Investigaciones Científicas, J. Girona 18-26, 08034 Barcelona, Spain. ampqob@iiqab.csic.es
Anna
A
Martínez-Cabot
Anna
A
Morató
Jan N M
JN
Commandeur
Nico P E
NP
Vermeulen
Angel
A
Messeguer
D000818:Animals; D001711:Biotransformation; D002384:Catalysis; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated; D005506:Food Contamination; D005517:Foodborne Diseases / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010938:Plant Oils / Q000633:toxicity*; D011409:Propylene Glycols / Q000378:metabolism / Q000633:toxicity; D011809:Quinones / Q000737:chemistry / Q000378:metabolism; D000074262:Rapeseed Oil; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism*; D013030:Spain / Q000453:epidemiology; D013379:Substrate Specificity; D013997:Time Factors
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D010938:Plant Oils; D011409:Propylene Glycols; D011809:Quinones; D000074262:Rapeseed Oil; D011994:Recombinant Proteins; C116897:iminoquinone; C077151:3-phenylamino-1,2-propanediol; D003577:Cytochrome P-450 Enzyme System