Inhibition of the glycine cleavage system: hyperglycinemia and hyperglycinuria caused by valproic acid.
Elevated amounts of glycine in serum and urine were demonstrated in patients and rats receiving the antiepileptic drug valproic acid. The hyperglycinuria in the patients was correlated to the dose of the anticonvulsant. The activity of the glycine cleavage system, the major catabolic pathway of glycine, in liver homogenates from rats treated with valproic acid was clearly reduced. Further in vitro studies on intact rat liver mitochondria and the solubilized glycine cleavage system showed that valproic acid and valproyl-CoA significantly inhibited the glycine cleavage enzyme complex. It was concluded that the hyperglycinemia and hyperglycinuria seen in patients and rats during the administration of valproic acid are due to the inhibition of the glycine cleavage system, most probably by valproic acid and/or valproyl-CoA.
D000818:Animals; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D005998:Glycine / Q000097:blood* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D014635:Valproic Acid / Q000009:adverse effects*
D014635:Valproic Acid; D005998:Glycine