Alterations in calcium homeostasis as a possible cause of Ochratoxin A nephrotoxicity

Chong, Xin (1993) Alterations in calcium homeostasis as a possible cause of Ochratoxin A nephrotoxicity. Masters thesis, Memorial University of Newfoundland.

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Abstract

The carcinogenic nephrotoxin Ochratoxin A (OTA) is a widespread natural contaminant of a variety of food and feedstuffs. The effect of OTA on renal lipid peroxidation and on renal cortical endoplasmic reticular ATP-dependent calcium uptake were investigated. -- OTA did not stimulate NADPH-dependent lipid peroxidation (malondialdehyde formation) in the kidney, either in vivo or in vitro. It also did not induce any of several antioxidative enzymes in vivo under our experimental conditions. Administration of a single high dose or multiple lower doses of OTA to rats did result in an increase of the renal cortical endoplasmic reticular ATP-dependent calcium pump activity. This increase was very rapid, being evident within 10 minutes of OTA administration, and remained elevated for at least 6 hours thereafter. This change in calcium uptake is the earliest enzymatic change reported in the kidney after OTA administration. -- In vitro preincubation of microsomes with NADPH had a profound inhibitory effect on calcium uptake. Inclusion of OTA was able to reverse the inhibition. Addition of OTA alone to cortical microsomes during calcium uptake inhibited the uptake process, although the effect was reversible. However, it does not appear that in vivo OTA exerts a significant direct inhibitory effect on renal cortical calcium uptake activity since an increase in this activity was observed after OTA administration. -- Changes in the rates of microsomal calcium uptake were correlated with changes in the steady-state levels of the phosphorylated Mg²⁺/Ca²⁺-ATPase intermediate suggesting that in vivo/in vitro conditions were affecting the rate of enzyme phosphorylation. -- Study of OTA analogues indicated that the presence of a free carboxyl group and chlorine atom on OTA contributed significantly to the effect on calcium uptake. -- These results suggest that lipid peroxidation may not be responsible for the initiating OTA nephrotoxicity. However, alterations in calcium homeostasis as evidenced by an increase in microsomal calcium pump activity could play a significant role in OTA nephrotoxicity.

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