Interactions between caffeine and adenosine agonists in producing embryo resorptions and malformations in mice.
Caffeine has previously been demonstrated to be teratogenic in mice, causing primarily limb reduction defects and cleft palate. To investigate the possibility that the mechanism of caffeine teratogenesis is related to its central stimulant activity, which is thought to result from its activity as an adenosine antagonist, the effects of the stable adenosine agonists L-phenylisopropyladenosine (L-PIA) and chloroadenosine on caffeine teratogenicity were examined. It was found that these adenosine analogs have embryolethal effects when administered intraperitoneally on Days 11 and 12 of gestation at extremely low dosages (minimal effect levels of 1 and 10 mumol/kg, respectively). Caffeine at dosages as low as 129 mumol/kg ip protected against the embryolethal effects of 5 mumol/kg L-PIA if administered simultaneously with L-PIA but not if administered 30 to 60 min after L-PIA. The maternotoxicity of either of the adenosine agonists or caffeine alone was ameliorated by coadministration of the other, particularly when the molar excess of caffeine was approximately 20-fold. These results suggest that the embryotoxicity and maternotoxicity of the adenosine agonists and the maternotoxicity of caffeine are mediated by binding to adenosine receptors. When coadministered with teratogenic dosages of caffeine (1160 to 1290 mumol/kg), L-PIA and chloroadenosine at dosage levels of 1 to 100 mumol/kg did not prevent and in some cases potentiated the teratogenic effects of caffeine. This lack of protection by L-PIA and chloroadenosine suggests that adenosine receptors are not the primary site of action for caffeine-induced teratogenicity. The embryolethal effects of L-PIA and chloroadenosine and the teratogenicity of caffeine occurred only at maternotoxic dosages. However, an analysis of the correlation structure indicates that the embryotoxicities of L-PIA and caffeine were not secondary to maternotoxicity as measured by body weight change.
Clark
R L
RL
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Eschbach
K
K
Cusick
W A
WA
Heyse
J F
JF
D015762:2-Chloroadenosine; D000014:Abnormalities, Drug-Induced / Q000188:drug therapy / Q000503:physiopathology*; D000241:Adenosine / Q000031:analogs & derivatives / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology / Q000633:toxicity*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D020964:Embryo Loss / Q000139:chemically induced*; D005260:Female; D005313:Fetal Death / Q000139:chemically induced*; D051379:Mice; D008815:Mice, Inbred Strains; D010660:Phenylisopropyladenosine / Q000633:toxicity; D011247:Pregnancy
D015762:2-Chloroadenosine; D010660:Phenylisopropyladenosine; D002110:Caffeine; D000241:Adenosine