Regulatory roles of high-affinity metal-binding proteins in mediating lead effects on delta-aminolevulinic acid dehydratase.
The present series of studies demonstrate that several high-affinity metal-binding proteins regulate essential metal availability and play a role in metal detoxication. Rat kidney PbBP and ZnMT were shown to mediate both the interaction of Zn and Pb to a Zn metalloenzyme, that is, ALAD. The mechanism for this interaction involves the donation of Zn from PbBP and ZnMT to ALAD and chelation of Pb to these proteins. In addition to activating ALAD via donation of Zn from ZnMT to the enzyme, kidney apothionein was shown to deactivate ALAD. Thus, these proteins may provide an intracellular reservoir for essential metals such as Zn and Cu, serving as a homeostatic control mechanism to readily dispense and sequester these cations to meet cellular metabolic requirements, such as the regulation of metalloenzymes, including ALAD. Although Pb does not effectively induce the synthesis of PbBP or ZnMT, these proteins, via binding of Pb, alter the biological activity of Pb toward a highly sensitive target molecule for Pb, that is, ALAD. Finally, when ALAD is utilized as a biological indicator for Pb exposure, the effect of ZnMT on Pb availability and ALAD activity must be taken into consideration. Tissue-specific differences in these high-affinity, metal-binding proteins and Zn status may alter the expected relationships between total tissue Pb concentrations and inhibition of ALAD.
Center for Devices and Radiological Health, Food and Drug Administration, Rockville, Maryland.
P L
PL
Goering
B A
BA
Fowler
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002352:Carrier Proteins / Q000378:metabolism*; D002417:Cattle; D003300:Copper / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007854:Lead / Q000378:metabolism* / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008668:Metallothionein / Q000378:metabolism*; D000623:Porphobilinogen Synthase / Q000378:metabolism*; D051381:Rats; D015032:Zinc / Q000378:metabolism
D002352:Carrier Proteins; C055217:lead-binding proteins; C021267:zinc thionein; D007854:Lead; D003300:Copper; D008668:Metallothionein; D000623:Porphobilinogen Synthase; D015032:Zinc