Inhibition of liver, kidney, and erythrocyte delta-aminolevulinic acid dehydratase (porphobilinogen synthase) by gallium in the rat.
Selective inhibition of enzymes in the heme biosynthesis pathway with concomitant urinary excretion of heme precursors serve as potentially important biological markers of chemical exposure and cell injury. Intratracheal administration of gallium arsenide particulate suspensions has been shown to result in inhibition of delta-aminolevulinic acid dehydratase (ALAD) in several tissues and increased excretion of the heme precursor aminolevulinic acid (ALA). This study was undertaken to evaluate in vivo the role of gallium alone in ALAD inhibition and increased urinary excretion of ALA. Male CD rats received a single ip injection of Ga2(SO4)3 at doses of 12.5, 25, 50, 100, and 200 mg Ga/kg. A dose-dependent inhibition of ALAD was observed 24 hr later in liver, kidney, and erythrocytes. After injection of 25 mg Ga/kg, maximal inhibition (42 to 49% of control) of ALAD occurred between 6 and 24 hr in liver and kidney with full recovery of activity at 96 hr. In erythrocytes, maximal inhibition (48% of control) occurred between 24 and 48 hr with recovery of activity at 96 hr. Mild to moderate renal proximal tubular necrosis in the pars recta was observed 24 hr after administration of 100 and 200 mg/kg, but no histopathologic changes were evident at lower doses. No consistent changes in urinary excretion of ALA were observed. Lineweaver-Burk analyses of renal and hepatic ALAD activities in the absence and presence of gallium indicated that the inhibition of ALAD by this element is noncompetitive (same Km, decreased Vmax). Gallium was shown to possess an inhibition constant (Ki) of approximately 3 microns for ALAD, similar to the Ki obtained for lead in other studies. Incubation of ALAD in vitro with gallium and lead, an active thiol group inhibitor, resulted in a greater inhibition of the enzyme. Further in vitro studies demonstrated the attenuation of gallium inhibition of hepatic and renal ALAD by zinc, suggesting that the mechanism of gallium action may involve competition for or displacement of zinc from the sulfhydryl group of the enzyme active site. Since ALAD inhibition occurred at doses at which no histopathologic changes were evident, the determination of ALAD activity in various tissues, including blood, may be of potential value as a biomarker of exposure/toxicity to metals such as gallium. The effect of chemical form and route of exposure of gallium and effects of other Group III metals on inhibition of ALAD and excretion of ALA is discussed.(ABSTRACT TRUNCATED AT 250 WORDS)
Goering
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PL
Division of Life Science, Food and Drug Administration, Rockville, Maryland 20857.
Rehm
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D000818:Animals; D004347:Drug Interactions; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology*; D005708:Gallium / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D007854:Lead / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D015032:Zinc / Q000494:pharmacology
D007854:Lead; D005708:Gallium; D000623:Porphobilinogen Synthase; D015032:Zinc