Effect of alpha interferon on glucose and alanine transport by rat renal brush border membrane vesicles.
To investigate the pathogenetic mechanisms of interferon nephrotoxicity, we studied the effect of recombinant interferon alfa-2b on the uptake of 14C-D-glucose and 14C-L-alanine by rat renal brush-border-membrane vesicles. Interferon significantly inhibited 20 sec. sodium-dependent and 5 and 10 min. equilibrium uptake of both glucose and alanine. The inhibitory effect was dose dependent with maximum effect achieved at interferon concentration of 5 X 10(-8)M in the uptake media. The half-maximal inhibitory concentrations, IC50, of interferon on glucose uptake was 1.8 X 10(-8)M, and 5.4 X 10(-9)M on alanine uptake. Dixon plot analysis of uptake data was consistent with pure non-competitive inhibition. The inhibition constants, Ki, 1.5 X 10(-8)M for glucose uptake, and 7.3 X 10(-9)M for alanine uptake, derived from Dixon plots were in close agreement with the IC50s calculated from the semilog dose response curves. These observations reveal that direct interactions at the proximal tubule cell membrane are involved in the pathogenesis of interferon nephrotoxicity, and that its mechanism of nephrotoxicity is similar to that of other low molecular weight proteins.
Batuman
V
V
Renal Section, Veterans Affairs Medical Center, East Orange, NJ 07019.
Chadha
I
I
D000409:Alanine / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002250:Carbon Radioisotopes; D005947:Glucose / Q000378:metabolism*; D066298:In Vitro Techniques; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins
D002250:Carbon Radioisotopes; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D005947:Glucose; D000409:Alanine