Toxicity of ochratoxin A, its opened lactone form and several of its analogs: Structure-activity relationships

被引:135
作者
Xiao, H
Madhyastha, S
Marquardt, RR
Li, SZ
Vodela, JK
Frohlich, AA
Kemppainen, BW
机构
[1] UNIV MANITOBA,DEPT ANIM SCI,WINNIPEG,MB R3T 2N2,CANADA
[2] AUBURN UNIV,COLL VET MED,DEPT PHYSIOL & PHARMACOL,AUBURN,AL 36849
基金
加拿大自然科学与工程研究理事会;
关键词
D O I
10.1006/taap.1996.0071
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 prokaryotic (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) for 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 inhibition 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 toxicities of OA were associated with its isocoumarin moiety but that neither the dissociation of the phenolic hydroxyl group nor the iron-chelating properties of OA were directly related to its toxicities. The lactone carbonyl group of OA, however, appears to be involved in OA toxicity as OP-OA is found in the bile of rats injected with OA and has similar toxicity to that of OA when administered intravenously to the rat. Overall, the structure-activity studies suggest that the toxicity of OA is attributable to its isocoumarin moiety and that the lactone carbonyl group may be involved in its toxicity. (C) 1996 Academic Press, Inc.
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页码:182 / 192
页数:11
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