Premium
In isolated rabbit renal proximal tubules, the antibiotic cephaloridine does not inhibit the mitochondrial uptake of succinate, a biomarker of its nephrotoxicity: A cellular metabolomic study with carbon 13 NMR
Author(s) -
Baverel Gabriel,
CadiSoussi Sophia,
Martin Guy
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.665.1
Subject(s) - cephaloridine , succinate dehydrogenase , biochemistry , malate dehydrogenase , mitochondrion , succinic acid , chemistry , nephrotoxicity , fumarase , enzyme , citrate synthase , metabolism , kidney , biology , endocrinology , antibiotics , cephalosporin
Cephaloridine is a model nephrotoxicant. In isolated rabbit renal mitochondria, cephaloridine (i) inhibits succinate uptake and (ii) reduces respiration. We have re‐examined this problem using isolated proximal tubules. Tubules were incubated in Krebs‐Henseleit buffer containing either 1,4‐ 13 C‐succinate, or 2,3‐ 13 C‐succinate or succinate + 13 C‐bicarbonate without or with cephaloridine. Substrate removal and product formation were measured by enzymatic and carbon 13 NMR methods. Enzymatic fluxes were calculated by combining these results with an original mathematical model of renal succinate metabolism. Succinate was converted mainly into fumarate, malate, glucose and CO 2 . Cephaloridine induced an increase in the accumulation of fumarate, malate and a decrease in the production of glucose, CO 2 and the level of ATP. Surprisingly, it did not change the removal of succinate. Fluxes through malate dehydrogenase, glucose 6‐phosphatase and citrate synthase were also diminished by cephaloridine. In conclusion, the absence of inhibition of mitochondrial uptake of succinate in intact renal proximal tubules strongly suggests that results obtained with isolated mitochondria do not necessarily apply to mitochondria in intact cells and, therefore, should be interpreted with great caution. These results also suggest that mitochondrial functions should be studied in intact cells.