Homocysteine inhibits retinoic acid synthesis: a mechanism for homocysteine-induced congenital defects.
Hyperhomocysteinemia is frequently associated with congenital defects of the heart and neural tube and is a suspected pathogenic factor in atherosclerosis and neoplasia. Results in the present report show homocysteine treatment disrupts normal development of avian embryos; and this effect is prevented by retinoic acid. Based on this, we hypothesize that homocysteine may exert its teratogenic effects by disrupting retinoic acid signaling during development. A reporter cell line transfected with a retinoic acid response element (RARE) linked to a lacZ reporter gene was used to identify the site of retinoid inhibition. Using this reporter cell line, we show that homocysteine inhibits the oxidation of retinal to retinoic acid with concentrations of homocysteine that are in the pathophysiological range (.05 to 0.5 mM). In contrast, homocysteine concentrations as high as 5 mM are unable to inhibit the induction of lacZ by retinoic acid. We show that cellular uptake of homocysteine is sensitive to the specific L-system transport inhibitor, bicycloheptane, and bicycloheptane blocks the inhibition of retinoic acid synthesis by homocysteine, demonstrating that this inhibition occurs intracellularly. These results suggest that homocysteine-induced congenital defects are due to the specific ability of homocysteine to inhibit conversion of retinal to retinoic acid.
Limpach
A
A
Department of Cell Biology and Anatomy, University of Nebraska Medical Center, 986395 Nebraska Medical Center, Omaha, Nebraska 68198, USA.
Dalton
M
M
Miles
R
R
Gadson
P
P
D000014:Abnormalities, Drug-Induced / Q000209:etiology* / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D002460:Cell Line; D002642:Chick Embryo; D017930:Genes, Reporter; D006710:Homocysteine / Q000378:metabolism / Q000633:toxicity*; D020138:Hyperhomocysteinemia / Q000150:complications / Q000378:metabolism; D007763:Lac Operon; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014212:Tretinoin / Q000378:metabolism*
D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D006710:Homocysteine; D014212:Tretinoin