TOXICITY OF OCHRATOXIN-A, ITS OPENED LACTONE FORM AND SEVERAL OF ITS ANALOGS - STRUCTURE-ACTIVITY-RELATIONSHIPS

Ochratoxin A (OA); its three natural analogs, ochratoxin C (OC), B (OB ), and alpha (O alpha); and its six synthetic analogs, the epimere of OA (d-OA), the ethylamide of OA (OE-OA), decarboxylated OA (DC-OA), O- methylated OA (OM-OA), lactone-opened OA (OP-OA), and the methyl ester of O alpha (M-O alpha) were assayed for their toxicities in prokaryot ic (Bacillus brevis) and eukaryotic (HeLa cell) systems and in animals (mouse and rat). The LC(50)s (mM) for HeLa cells, were 0.005 (OA), 0. 009 (OC), 0.163 (d-OA), 10.1 (OE-OA), 7.6 (DC-OA), 0.83 (OM-OA), 0.054 (OB), and 0.56 (O alpha). The minimum inhibitory doses (nmol/disc) fo r the growth of B. brevis (pH 6.5) were 8.7 (OA), 2.0 (OC), 5.5 (d-OA) , 1.1 (OE-OA), 54 (OB), 390 (O alpha), and 90 (M-O alpha) while no inh ibition of the bacterial growth was observed for OM-OA, DC-OA, and OP- OA at doses as high as 350 nmol/disc. The results indicate that the to xicities of OA were associated with its isocoumarin moiety but that ne ither the dissociation of the phenolic hydroxyl group nor the iron-che lating properties of OA were directly related to its toxicities. The l actone carbonyl group of OA, however, appears to be involved in OA tox icity as OP-OA is found in the bile of rats injected with OA and has s imilar toxicity to that of OA when administered intravenously to the r at. Overall, the structure-activity studies suggest that the toxicity of OA is attributable to its isocoumarin moiety and that the lactone c arbonyl group may be involved in its toxicity. (C) 1996 Academic Press , Inc.