Hepatic glucocorticoid receptors and the H–2 locus

Abstract

VARIOUS inbred strains of mice exhibit different degrees of susceptibility to both spontaneous and glucocorticoid-induced cleft palate^1,2, and specific genetic and biochemical factors that may be responsible for these differences have been identified. At the genetic level, variations at the H–2 locus have been associated with susceptibility to glucocorticoid-induced cleft palate^3,4, while at the biochemical level, evidence suggests that numbers and characteristics of glucocorticoid receptors in murine embryonic facial mesenchyme cells differ in the various strains. Specifically, Salomon and Pratt showed that facial mesenchyme cells cultured from fetuses of the A/J strain (which is highly susceptible to glucocorticoid-induced cleft palate) contain twice as many glucocorticoid receptors as do such cells from C57BL/6J, a low susceptibility strain⁵. They also reported that the glucocorticoid receptor of the A/J strain has a lower affinity for dexamethasone (K_D = 1.7 × 10⁻⁸ M) than does that of the C57BL/6J strain (K_D = 7.9 × 10⁻⁹M) (ref. 5). In an attempt to relate steroid receptor activity to H–2 haplotype, Goldman et al. used ³H-cortisol and isoelectric focusing to study glucocorticoid receptors in facial mesenchyme cells of these and several other strains⁶. They concluded that “a product of a gene in or near the H–2 locus seems to be the glucocorticoid receptor, the level of which must be increased for a congenital malformation to occur”. Such conclusions must be questioned, however, because the experimental procedure required microelectrofocusing of isolated protein–cortisol complex for 40 h. Receptor binding is reversible, and in the absence of free steroid, the half life of the receptor–cortisol complex is only about 1 h at 0 °C (ref. 7). It is unlikely that a peak of radioactivity detected by isoelectric focusing after 40 h represents binding to a specific receptor. Thus an association between H–2 haplotype and glucocorticoid receptor activity has not been established definitively. However, the possibility that H–2 might determine hormone receptor levels or characteristics is exciting. We have explored the relationship between H–2 and glucocorticoid receptors by examining the level of specific glucocorticoid-binding activity in liver cytosols prepared from different mouse strains.