Effect of intratracheal gallium arsenide administration on delta-aminolevulinic acid dehydratase in rats: relationship to urinary excretion of aminolevulinic acid.
Exposure to gallium arsenide (GaAs) is a potential hazard in the semiconductor industry and there is a need for specific biological indicators of exposure/toxicity for this compound. These studies examined effects of GaAs exposure on the heme biosynthetic pathway enzyme delta-aminolevulinic acid dehydratase (ALAD). Male CD rats received GaAs suspensions at doses of 50, 100, or 200 mg/kg via a single intratracheal instillation. Six days after treatment a dose-dependent inhibition of blood ALAD was observed with activity decreasing to 5% of controls at the highest dose, with a concomitant marked increase in the urinary excretion of aminolevulinic acid (ALA). Inhibition of blood ALAD following administration of GaAs was maximal (30% of control) 3 to 6 days postexposure and returned to approximately control values on day 18. Urinary excretion of ALA was maximal 3 to 6 days postexposure and recovered toward control values at 18 days. Inhibition of kidney and liver ALAD following GaAs exposure was also evident. Intratracheal instillation of silica did not alter the activity of ALAD in blood, liver, or kidney. Marked increases in lung wet weight/body weight ratios were evident in lungs of silica- and GaAs-treated rats. Histopathological changes in the lungs were characterized by multifocal granulomas following silica treatment and Type II pneumocyte hyperplasia following GaAs treatment; mild necrosis was evident in both groups. Rats treated with 100 mg/kg GaAs exhibited swelling of kidney proximal tubule mitochondria 6 days following exposure. Silica and GaAs exposure produced marked decreases in cumulative weight gain. The concentration of gallium required to achieve half-maximal inhibition of ALAD in vitro was 200-fold less in blood and 40-fold less in kidney and liver than that required for arsenite and the inhibition was partially prevented by excess zinc. These data suggest that gallium is the primary inhibitor of ALAD following dissolution of GaAs in vivo and that competition for or displacement of zinc from the enzyme active site may be involved in the mechanism of inhibition. The data also demonstrated the utility of including a particulate control group when assessing the chemical-induced toxicity of compounds administered intratracheally as particulate suspensions. Finally, measurement of heme precursors, e.g., ALA, in urine coupled with assay of red blood cell ALAD activity may be of value as an early biological indicator of GaAs exposure and/or toxicity.
Goering
P L
PL
National Institute of Enviromental Health Sciences, Research Triangle Park, North Carolina 27709.
Maronpot
R R
RR
Fowler
B A
BA
D000622:Aminolevulinic Acid / Q000652:urine*; D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D001152:Arsenicals; D004305:Dose-Response Relationship, Drug; D005708:Gallium / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D007982:Levulinic Acids / Q000652:urine*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D000623:Porphobilinogen Synthase / Q000097:blood / Q000378:metabolism*; D051381:Rats
D001152:Arsenicals; D007982:Levulinic Acids; C043055:gallium arsenide; D000622:Aminolevulinic Acid; D005708:Gallium; D000623:Porphobilinogen Synthase; D001151:Arsenic