Comparison of nicotinic receptor binding and biotransformation of coniine in the rat and chick.
Coniine, an alkaloid from Conium maculatum (poison hemlock), is a known teratogen in many domestic species with maternal ingestion resulting in arthrogryposis of the offspring. We have previously shown that rats are not susceptible and rabbits only weakly susceptible to coniine-induced arthrogryposis. However, the chick embryo does provide a reproducible laboratory animal model of coniine-induced teratogenesis. The reason for this cross-species variation is unknown. The purpose of this study was to evaluate coniine binding to nicotinic receptors and to measure coniine metabolism in vitro between susceptible and non-susceptible species. Using the chick model, neither the peripheral nicotinic receptor antagonist d-tubocurarine chloride nor the central nicotinic receptor antagonist trimethaphan camsylate blocked the teratogenesis or lethality of 1.5% coniine (50 microliters/egg). Trimethaphan camsylate enhanced coniine-induced lethality in a dose-dependent manner. Neither nicotinic receptor blocker prevented nicotine sulfate-induced malformations but d-tubocurarine chloride did block lethality in a dose-dependent manner. Competition by coniine for [125I]-alpha-bungarotoxin to nicotinic receptors isolated from adult rat diaphragm and chick thigh muscle and competition by coniine for [3H]-cytisine to receptors from rat and chick brain were used to assess coniine binding to nicotinic receptors. The IC50 for coniine in rat diaphragm was 314 microM while that for chick leg muscle was 70 microM. For neuronal nicotinic receptors, the IC50s of coniine for maternal rat brain, fetal rat brain, and chick brain were 1100 microM, 820 microM, and 270 microM, respectively. There were no differences in coniine biotransformation in vitro by microsomes from rat or chick livers. Differences in apparent affinity of coniine for nicotinic receptors or differences in the quantity of the nicotinic receptor between the rat and chick may explain, in part, the differences in susceptibility of coniine-induced teratogenesis between these two species.
Forsyth
C S
CS
Biomedical and Environmental Information Analysis Section, Oak Ridge National Laboratory, TN 37830, USA.
Speth
R C
RC
Wecker
L
L
Galey
F D
FD
Frank
A A
AA
D000014:Abnormalities, Drug-Induced / Q000378:metabolism*; D000470:Alkaloids / Q000493:pharmacokinetics* / Q000633:toxicity; D000700:Analgesics / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002642:Chick Embryo; D004625:Embryo, Nonmammalian / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000493:pharmacokinetics*; D010880:Piperidines; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate
D000470:Alkaloids; D000700:Analgesics; D018733:Nicotinic Antagonists; D010880:Piperidines; C007112:coniine