Regulation of lead inhibition of delta-aminolevulinic acid dehydratase by a low molecular weight, high affinity renal lead-binding protein.
The bioavailability of Pb in kidney is mediated in part by binding to high affinity cytosolic Pb-binding proteins (PbBP) of 11,500 (11.5K) and 63,000 (63K) daltons, which are not found in liver. Renal delta-aminolevulinic acid dehydratase (ALAD) is also markedly more resistant to Pb inhibition than hepatic ALAD in vivo. This study was undertaken to evaluate further the differences in sensitivity of renal and hepatic ALAD to Pb and to determine if inhibition of hepatic ALAD by Pb could be reversed by addition of partially purified PbBP from kidney to liver cytosol. Rat liver or kidney cytosol was incubated with Pb over a concentration range of 0.1 to 10 microM. Renal ALAD was 7.5 times more resistant to Pb inhibition than that in liver. Kidney cytosol and 203Pb were incubated before Sephadex G-75 or G-150 column chromatography to isolate the 11.5K and 63K PbBP, respectively. Inhibition of hepatic ALAD activity by Pb was partially reversed by a single addition of semipurified 11.5K PbBP in the presence of 0.1 to 0.4 microM Pb, but no protective effect was observed at higher concentrations of Pb. This effect was not observed with the 63K PbBP added at an equivalent high affinity binding capacity or bovine serum albumin added at an 8-fold higher total protein concentration. Reversal of Pb-induced inhibition of hepatic ALAD activity was dependent on the concentration of 11.5K PbBP in the reaction mixture. Kinetic analysis of either hepatic or renal ALAD activity at an IC50 concentration of Pb indicated a noncompetitive inhibition pattern.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology*; D002479:Inclusion Bodies / Q000502:physiology; D007668:Kidney / Q000201:enzymology*; D007700:Kinetics; D007854:Lead / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology; D008297:Male; D008970:Molecular Weight; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors*; D051381:Rats
D002352:Carrier Proteins; D007854:Lead; D000623:Porphobilinogen Synthase