Penetration of endogenous steroid hormones corticosterone, cortisol, aldosterone and progesterone into the brain is enhanced in mice deficient for both mdr1a and mdr1b P-glycoproteins.
Numerous investigations have confirmed an important role for multidrug-resistance gene 1-type P-glycoproteins (MDR1-type P-gps) in the blood-brain barrier, protecting the brain against the accumulation of a wide range of toxic xenobiotics and drugs. Several studies have provided evidence in vitro that certain steroid hormones are transported by MDR1-type P-gps; however, the question of whether this might also apply to the situation in vivo still remained to be determined. We used mice deficient for both murine mdr1a and mdr1b P-gps [mdr1a/1b(-/-)] to determine the uptake of [3H]-cortisol, [3H]-corticosterone, [3H]-aldosterone and [3H]-progesterone into the plasma, brain, testes, liver, spleen, pituitary and adrenal glands. We provide evidence that the access of the endogenous steroid hormones corticosterone, cortisol and aldosterone is regulated by MDR1-type P-gps in vivo. As peripherally administered steroid hormones accumulate in the brain of mice deficient for MDR1-type P-gps, mdr1a/1b proteins are likely to transport these hormones out of the brain, providing a kinetic barrier to their entry. Intracerebral progesterone concentrations are influenced by MDR1-type P-gp function as well; however, the effects are only small. In addition, all four endogenous glucocorticoid hormones accumulated in the testes of mdr1a/1b(-/-) mice. Our findings underline the importance of MDR1-type P-gps as an endogenous barrier system controlling the access of endogenous steroid hormones at the blood-brain barrier to maintain homeostatic control and to protect central nervous system neurones.
Uhr
M
M
Max Planck Institute of Psychiatry, Munich, Germany. uhr@mpipsykl.mpg.de
Holsboer
F
F
Müller
M B
MB
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000311:Adrenal Glands / Q000378:metabolism; D000450:Aldosterone / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000502:physiology*; D003345:Corticosterone / Q000737:chemistry / Q000493:pharmacokinetics*; D006854:Hydrocortisone / Q000737:chemistry / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010902:Pituitary Gland / Q000378:metabolism; D011374:Progesterone / Q000737:chemistry / Q000493:pharmacokinetics*; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution; D014316:Tritium; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000450:Aldosterone; D000893:Anti-Inflammatory Agents; D003345:Corticosterone; D006854:Hydrocortisone; D011374:Progesterone; D014316:Tritium; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3