High-affinity renal lead-binding proteins in environmentally-exposed humans.
Chronic low level lead (Pb) exposure is associated with decrements in renal function in humans, but the molecular mechanisms underlying toxicity are not understood. We investigated cytosolic Pb-binding proteins (PbBP) in kidney of environmentally-exposed humans to identify molecular targets of Pb and elucidate mechanisms of toxicity. This study is unique in that it localized PbBPs based on physiologic Pb that was bound in vivo. Two Pb-binding polypeptides were identified, thymosin beta 4 (T beta 4, 5 kDa) and acyl-CoA binding protein (ACBP, 9 kDa, also known as diazepam binding inhibitor, DBI). These polypeptides, which have not been previously recognized for their metal-binding capabilities, were shown to bind Pb with high affinity (Kd approximately 14 nM) and to account for an estimated > 35% of the total Pb in kidney cortex tissue. Both T beta 4 and ACBP (DBI) occur across animal species from invertebrates to mammals and in all major tissues, serving multiple possible functions (e.g. regulation of actin polymerization, calmodulin-dependent enzyme activity, acyl-CoA metabolism, GABA-A/benzodiazepine receptor modulation, steroidogenesis, etc.). Thus, these data provide the first evidence of specific molecular targets of Pb in kidney of environmentally-exposed humans, and they suggest that low-level Pb toxicity may occur via alteration of T beta 4 and ACBP (DBI) function in renal and other tissues, including the central nervous system.
Smith
D R
DR
Biology and Environmental Toxicology, University of California, Santa Cruz 95064, USA. dsmith@biology.ucsc.edu
Kahng
M W
MW
Quintanilla-Vega
B
B
Fowler
B A
BA
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000302:isolation & purification* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D026261:Diazepam Binding Inhibitor; D004591:Electrophoresis, Polyacrylamide Gel; D004781:Environmental Exposure; D006801:Humans; D007672:Kidney Cortex / Q000378:metabolism*; D007854:Lead / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D013947:Thymosin / Q000737:chemistry / Q000302:isolation & purification* / Q000378:metabolism; D000099201:Thymosin beta(4)
D002352:Carrier Proteins; D026261:Diazepam Binding Inhibitor; D007854:Lead; D013947:Thymosin; D000099201:Thymosin beta(4); C055217:lead-binding proteins