In vivo effects of triorganotins on calmodulin activity in rat brain.
We have recently reported that the triorganotins are effective inhibitors of calmodulin (CaM) activity in vitro. The present experiments were designed to investigate the in vivo effects of triorganotins, that is, tributyltin (TBT), triethyltin (TET), and trimethyltin (TMT) on rat brain CaM activity. Male Sprague-Dawley rats were treated orally with TET (0.5, 1.0, and 1.5 mg/kg/d), TMT (0.75, 1.50, and 2.50 mg/kg/d), and TBT (0.75, 1.50, and 2.50 mg/kg/d) for 6 d and they were sacrificed 24 h after the last dose. There was significant loss of body weight in the high-dose group of the organotin treated rats. Ca(2+)-ATPase activity was determined in rat brain synaptic membranes. TET and TMT inhibited Ca(2+)-ATPase in a dose-dependent manner but TBT exhibited its inhibitory effect only at the highest dose (2.5 mg/kg/d). The inhibition of Ca(2+)-ATPase by these triorganotin compounds was reversed to control levels by the addition of CaM (5-10 micrograms) exogenously. The CaM levels of the synaptic membranes of the organotin-treated rats were not significantly changed. The data presented in this paper demonstrate that triorganotins impair the Ca(2+)-pump activity by interacting with CaM, which is a regulatory protein of Ca(2+)-ATPase. The present in vivo data and our previously reported in vitro data together indicate that triorganotins associated neurotoxicity may be due to an altered CaM activity in brain.
Yallapragada
P R
PR
Department of Neurology, University of Mississippi Medical Center, Jackson 39216.
Vig
P J
PJ
Kodavanti
P R
PR
Desaiah
D
D
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009947:Organotin Compounds / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013570:Synaptic Membranes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
D002147:Calmodulin; D009947:Organotin Compounds; D000252:Calcium-Transporting ATPases