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

• Published in: Chemical research in toxicology Vol. 20; no. 8; pp. 1218 - 1224
• Main Authors: Martínez-Cabot, Anna, Morató, Anna, Commandeur, Jan N. M, Vermeulen, Nico P. E, Messeguer, Angel
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-08-2007
• Subjects: Animals; Biotransformation; Canola Oil; Catalysis; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Enzyme Inhibitors - pharmacology; Fatty Acids, Monounsaturated; Food Contamination; Foodborne Diseases - epidemiology; Foodborne Diseases - metabolism; Foodborne Diseases - pathology; Humans; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Oxidation-Reduction; Plant Oils - toxicity; Propylene Glycols - metabolism; Propylene Glycols - toxicity; Quinones - chemistry; Quinones - metabolism; Rats; Recombinant Proteins - metabolism; Spain - epidemiology; Substrate Specificity; Time Factors
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx700209p

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.