Alkyltin inhibition of ATPase activities in tissue homogenates and subcellular fractions from adult and neonatal rats.
Inhibition of ATPase activities by triethyltin (TET), diethyltin (DET), monoethyltin (MET), and trimethyltin (TMT) was studied in homogenates of brain and liver from adult and neonatal rats. In the adult, sensitivities were as follows: mitochondrial ATPase of liver much greater than Na+, K+-ATPase of brain approximately equal to mitochondrial ATPase of brain greater than nonspecific ATPase of brain and liver. MET did not produce significant inhibition. ATPase activities in brain and liver homogenates from TET-treated adult rats did not differ from controls. Mitochondrial ATPase in brain homogenates from 5-day-old rats was two orders of magnitude more sensitive to TET than brain homogenates from adult rats (IC50 of 2.5 microM in the 5-day-old neonate vs 260 microM in the adult). By contrast, isolated mitochondria and synaptosomal fractions from adult and neonatal brains were equally sensitive to TET (IC50 = 1-3 microM). At 10 days of age, following the onset of myelination, the IC50 for TET inhibition of brain mitochondrial ATPase increased to 71 microM. Myelin added directly to isolated mitochondria also reduced TET-induced inhibition. It is concluded that in vivo brain tin concentrations in 5-day-old rats following a neurotoxic dose of TET are sufficient to inhibit brain mitochondrial ATPase, whereas in adults, tin concentrations are insufficient for inhibition. In the adult rat, TET binding to myelin appears to prevent inhibition of brain mitochondrial ATPase, and the target of toxic action may be myelin. In the neonateal rat, TET may inhibit oxidative phosphorylation in unmyelinated brain tissue, leading to neuronal cell death.
Stine
K E
KE
Curriculum in Toxicology, University of North Carolina, Chapel Hill 27599.
Reiter
L W
LW
Lemasters
J J
JJ
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D009186:Myelin Sheath / Q000378:metabolism; D051381:Rats; D014220:Trialkyltin Compounds / Q000378:metabolism / Q000633:toxicity*
D014220:Trialkyltin Compounds; D000251:Adenosine Triphosphatases