Document Detail


Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice.
MedLine Citation:
PMID:  9717696     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A subpopulation of the CF-1 mouse strain contains a spontaneous mutation in the P-glycoprotein (Pgp) mdr1a gene, which leads to a lack of mdr1a expression in the placenta as well as brain and intestine. Individual CF-1 mice can be identified according to their Pgp status by a restriction fragment length polymorphism. Male and female mice selected on the basis of Pgp genotype were mated and the pregnant dams exposed during gestation to the known Pgp substrate, L-652,280, the 8,9 Z photoisomer of the naturally occurring avermectin Bla, which is known to produce cleft palate in mice. Fetal examination demonstrated that within individual litters, fetuses deficient in Pgp (-/-) were 100% susceptible to cleft palate, whereas their +/- heterozygote littermates were less sensitive. The homozygous +/+ fetuses with abundant Pgp were totally insensitive at the doses tested. The degree of chemical exposure of fetuses within each litter was inversely related to expression of placental Pgp, which was determined by the fetal genotype. These results demonstrate the importance of placental Pgp in protecting the fetus from potential teratogens and suggest that Pgp inhibitors should be carefully evaluated for their potential to increase susceptibility to chemical-induced teratogenesis.
Authors:
G R Lankas; L D Wise; M E Cartwright; T Pippert; D R Umbenhauer
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Reproductive toxicology (Elmsford, N.Y.)     Volume:  12     ISSN:  0890-6238     ISO Abbreviation:  Reprod. Toxicol.     Publication Date:    1998 Jul-Aug
Date Detail:
Created Date:  1998-10-15     Completed Date:  1998-10-15     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  8803591     Medline TA:  Reprod Toxicol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  457-63     Citation Subset:  IM    
Affiliation:
Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. lankas@merck.com
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MeSH Terms
Descriptor/Qualifier:
Abnormalities, Drug-Induced / etiology*
Animals
Cleft Palate / chemically induced
Female
Genotype
Ivermectin / analogs & derivatives,  toxicity
Male
Mice
P-Glycoprotein / deficiency*,  genetics,  physiology
Placenta / metabolism*
Pregnancy
Chemical
Reg. No./Substance:
0/P-Glycoprotein; 70288-86-7/Ivermectin; 73989-17-0/avermectin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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