H-2 influences phenytoin binding and inhibition of prostaglandin synthesis.
We have reported that susceptibility to glucocorticoid- and phenytoin-induced cleft palate and glucocorticoid receptor levels in mice are influenced by the H-2 histocompatibility complex on chromosome 17. Phenytoin competes with glucocorticoids for the glucocorticoid receptor and inhibits production of prostaglandins and thromboxanes. In this paper we have investigated whether, as in the case of glucocorticoids, phenytoin receptor levels and phenytoin-induced inhibition of prostaglandins are influenced by H-2 in a variety of mouse tissues. Using congenic strains varying only in the H-2 region, but otherwise having either the A/Wy(A) or B10(B) genetic background, we demonstrate here that phenytoin receptor content in the lung and liver is significantly higher in the strains with H-2a (A/Wy and B10.A) than in their corresponding H-2b partners (A.BY and B10). The H-2 complex also influences phenytoin-induced inhibition of the release of 3H-arachidonic acid and prostaglandin biosynthesis from thymocytes, prelabeled with 3H-arachidonic acid. Thus, these results suggest a similar genetic and biochemical pathway for the teratogenic action of both phenytoin and glucocorticoids.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D008040:Genetic Linkage; D005938:Glucocorticoids / Q000494:pharmacology; D006183:H-2 Antigens / Q000235:genetics*; D051379:Mice; D010672:Phenytoin / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D011955:Receptors, Drug / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics*; D013601:T-Lymphocytes / Q000187:drug effects; D013931:Thromboxanes / Q000096:biosynthesis
D001095:Arachidonic Acids; D005938:Glucocorticoids; D006183:H-2 Antigens; D010743:Phospholipids; D011453:Prostaglandins; D011955:Receptors, Drug; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D013931:Thromboxanes; C029450:phenytoin receptor; D016718:Arachidonic Acid; D010672:Phenytoin; D003907:Dexamethasone