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Lipid peroxidation as a possible cause of ochratoxin A toxicity
A D Rahimtula1, J C Béréziat, V Bussacchini-Griot
1International Agency for Research on Cancer, Lyon, France.
Abstract:
Addition of the mycotoxin ochratoxin A (OA), a nephrotoxic carcinogen, to rat liver microsomes greatly enhanced the rate of NADPH or ascorbate-dependent lipid peroxidation as measured by malondialdehyde formation. NADPH-dependent lipid peroxidation in kidney microsomes was similarly enhanced by OA. The process required the presence of trace amounts of iron but cytochrome P-450 and free active oxygen species appeared not to be involved. The efficiency of several ochratoxins (ochratoxins A, B, C, alpha and O-methyl-ochratoxin C) to enhance lipid peroxidation was related to the presence and reactivity of the phenolic hydroxyl group. Furthermore, the ability of these ochratoxins to enhance lipid peroxidation in microsomes correlated precisely with their known toxicities in chicks. Administration of ochratoxin A to rats also resulted in enhanced lipid peroxidation in vivo as evidenced by a seven-fold increase in the rate of ethane exhalation. These results suggest that lipid peroxidation may play a role in the observed toxicity of ochratoxin A in animals; a mechanism is proposed. (Formula: see text). Ochratoxin A: X = Cl; R1 = R2 = R3 = R4 = H Ochratoxin B: X = H; R1 = R2 = R3 = R4 = H Ochratoxin C: X = Cl; R1 = R2 = R3 = H; = R4 = CH3 O-Methyl-ochratoxin C: X = Cl; R2 = R3 = H; R1 = R4 = CH3 (4R)-4-hydroxyochratoxin A: X = Cl; R1 = R3 = R4 = H; R2 = OH (4S)-4-hydroxyochratoxin A: X = Cl; R1 = R2 = R4 = H; R3 = OH Fig. 1. Chemical structures of the various ochratoxins.
Insights
The mycotoxin ochratoxin A (OA) significantly increases lipid peroxidation in rat liver and kidney microsomes, a process dependent on iron. This enhanced lipid peroxidation correlates with OA
Area of Science:
- Toxicology
- Biochemistry
- Mycotoxicology
Background:
- Ochratoxin A (OA) is a nephrotoxic and carcinogenic mycotoxin.
- Lipid peroxidation is a damaging process implicated in various toxicities.
- The precise mechanisms by which OA exerts its toxicity are not fully elucidated.
Purpose of the Study:
- To investigate the effect of ochratoxin A on lipid peroxidation in rat liver and kidney microsomes.
- To explore the role of iron and active oxygen species in OA-induced lipid peroxidation.
- To correlate the mycotoxin's structure with its ability to induce lipid peroxidation and its known toxicity.
Main Methods:
- Incubation of rat liver and kidney microsomes with ochratoxin A and NADPH or ascorbate.
- Measurement of malondialdehyde formation as an indicator of lipid peroxidation.
- Assessment of the requirement for iron, cytochrome P-450, and active oxygen species.
- Evaluation of various ochratoxin analogues for their ability to enhance lipid peroxidation.
- Measurement of ethane exhalation in rats treated with ochratoxin A in vivo.
Main Results:
- Ochratoxin A significantly enhanced NADPH- and ascorbate-dependent lipid peroxidation in both liver and kidney microsomes.
- The process required trace amounts of iron but did not involve cytochrome P-450 or active oxygen species.
- The efficiency of ochratoxins in enhancing lipid peroxidation correlated with their phenolic hydroxyl group and their known toxicities in chicks.
- In vivo administration of ochratoxin A to rats resulted in a seven-fold increase in ethane exhalation, indicating enhanced lipid peroxidation.
Conclusions:
- Lipid peroxidation is a key mechanism contributing to the toxicity of ochratoxin A in animals.
- The structure of ochratoxin, particularly the phenolic hydroxyl group, influences its pro-oxidant activity.
- Further research into the proposed mechanism of OA-induced lipid peroxidation is warranted.