| First Author | Okey AB | Year | 1989 |
| Journal | Mol Pharmacol | Volume | 35 |
| Issue | 6 | Pages | 823-30 |
| PubMed ID | 2543914 | Mgi Jnum | J:27899 |
| Mgi Id | MGI:75534 | Citation | Okey AB, et al. (1989) Detection and characterization of a low affinity form of cytosolic Ah receptor in livers of mice nonresponsive to induction of cytochrome P1-450 by 3-methylcholanthrene. Mol Pharmacol 35(6):823-30 |
| abstractText | Ah nonresponsive mice (prototype, DBA/2) show no significant increase in hepatic P1-450 (P450IA1) when treated with 3-methylcholanthrene or other nonhalogenated polycyclic aromatic hydrocarbons. Potent halogenated aromatics such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induce P1-450 in liver of nonresponsive mice, but the dose required is approximately 15-fold higher than in responsive mice (prototype, C57BL/6). It was postulated several years ago that the genetic basis of nonresponsiveness was a defect in the Ah receptor, which normally binds TCDD and other inducers and mediates the induction process. Cytosolic Ah receptor hitherto had not been detectable in hepatic cytosol from nonresponsive mice. Using a modified sucrose gradient assay that we developed in studies on human tissue [Cancer Res. 47:4861-4868 (1987)], we now have detected cytosolic Ah receptor in nonresponsive mice. By saturation analysis, the concentration of specific binding sites for [3H]TCDD in hepatic cytosol from DBA/2J mice was (mean +/- SE) 55 +/- 6.6 fmol/mg of cytosolic protein (n = 21) compared with 133 +/- 7.1 fmol/mg (n = 21) in responsive C57BL/6J mice. Ah receptor also was detected in significant concentrations in other nonresponsive strains; SWR/J, AKR/J, RF/J, and DBA/2N. The sedimentation coefficient on sucrose gradients was the same (approximately 9 S) in nonresponsive as in responsive strains. The major difference in nonresponsive mice is that hepatic cytosolic Ah receptor has an apparent affinity for [3H]TCDD that is about 10-fold lower than in responsive strains; Kd in DBA/2J mice = 16 +/- 2.5 nM (n = 21) and Kd in C57BL/6J mice = 1.8 +/- 0.2 nM (n = 21). Thus, nonresponsive mice do possess the cytosolic Ah receptor in liver. However, the receptor is present in reduced concentration and appears to be a low affinity form, possibly as the result of a mutation in the gene(s) coding for the receptor protein(s). |
