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 (Oalpha); 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 Oalpha (M-Oalpha) were assayed for their toxicities in prokaryotic (Bacillus brevis) and eukaryotic (HeLa cell) systems and in animals (mouse and rat). The LC50S (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 Oalpha). 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 (Oalpha), and 90 (M-Oalpha) 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.
Xiao
H
H
Department of Animal Science, University of Manitoba, Winnipeg, Canada.
Madhyastha
S
S
Marquardt
R R
RR
Li
S
S
Vodela
J K
JK
Frohlich
A A
AA
Kemppainen
B W
BW
D000818:Animals; D001407:Bacillus / Q000187:drug effects; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D007502:Iron Chelating Agents / Q000378:metabolism / Q000494:pharmacology; D007783:Lactones / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D008826:Microbial Sensitivity Tests; D009793:Ochratoxins / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D007502:Iron Chelating Agents; D007783:Lactones; D009793:Ochratoxins; C025589:ochratoxin A