igure 8.10. Membrane topology of ASBT. Hydropathy analysis proposes a seven transmembrane topology for ASBT. Studies with antibodies to terminal epitopes have confirmed the inside-out ientation of this membrane protein.

tionships in humans; however, no correlation was observed between KT values and conjugation.

3. Fo r efficient transport, a bile acid molecule must possess a single negative charge (276) that should be located on the C-17 side-chisin of the sterol nucleus (277).

4. Although bile acids with two negative charges around the C-17 position give minim al active transport, the addition of an extra negative charge in the form of sulfon-ation at the C-3 position does not preclude active transport (278). Replacing the anionic moiety from the C-17 side-chain to position 3 results in a complete loss of affinity (277).

5. Stereospecificity of the hydroxyl groups on the sterol nucleus was shown by substitution of this group at the 3-position with a hydroxyethoxy moiety (279). The 3a-iso-mer was able to inhibit transport of [3H]taurocholate in rabbit ileal brush-bor-deimembrane vesicles, whereas the 3j3-iso-

mer showed very weak affinity and was unable to inhibit taurocholic acid transport.

Lack and coworkers have proposed that the recognition site for carrier-mediated bile acid transport is a hydrophobic pocket on the membrane surface that consists of three components: a recognition site for interaction with the steroid nucleus; a cationic site for coulom-interaction with the negatively charged side chain; and an anionic site for interaction with Na+. Supposedly, this anionic site could be responsible for the reduced affinity of bile acid derivatives with a dianionic side chain (280). Generalizations on the structural requirements for ASBT affinity include:

1. The presence of at least one hydroxyl group on the steroid nucleus at position 3, 7, or 12.

2. A single negative charge in the general vicinity of the C-17 side-chain; however, an

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