Mechanism of pH amelioration of 2-bromohydroquinone-induced toxicity to rabbit renal proximal tubules.
The basis of extracellular acidosis amelioration of 2-bromohydroquinone (BHQ)-induced renal proximal tubular cell death was determined by comparing the metabolism, uptake and mitochondrial effects of BHQ (0.2 mM) and bromoquinone (BQ) (0.05 mM) on isolated rabbit renal proximal tubules incubated in pH 7.4 and pH 6.4 buffers. Exposure of proximal tubules in pH 7.4 buffer to [14C]BHQ resulted in a time-dependent increase in covalently bound BHQ-equivalents to tubular protein (9 +/- 1 nmol/mg of protein at 1 hr) and a decrease in nystatin-stimulated oxygen consumption (NYS-QO2). In comparison, covalently bound BHQ-equivalents were 0.7 nmol/mg of protein and NYS-QO2 was unaffected in proximal tubules incubated at pH 6.4 for 1 hr. After a 1-hr exposure, tubular content of [14C]BHQ-equivalents was 15 +/- 2 and 9 +/- 1 nmol/mg of protein in tubules incubated at pH 7.4 and 6.4, respectively. Thus, decreased covalent binding of BHQ-equivalents in proximal tubules incubated at pH 6.4 could not be accounted for by limited uptake of BHQ. The lactate dehydrogenase release induced by 0.05 mM BQ was decreased by acidic pH. Similarly, BQ induced an 85% decrease in NYS-QO2 of proximal tubules in pH 7.4 buffer, compared to a 55% inhibition when proximal tubules were incubated at pH 6.4 for 4 hr. Thus, extracellular acidosis ameliorates BHQ toxicity by altering BHQ biotransformation; that is, extracellular acidosis inhibits the oxidation of BHQ to BQ and may promote the reduction of BQ to BHQ.[1]References
- Mechanism of pH amelioration of 2-bromohydroquinone-induced toxicity to rabbit renal proximal tubules. Rodeheaver, D.P., Schnellmann, R.G. J. Pharmacol. Exp. Ther. (1991) [Pubmed]
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