Effect of acivicin on glutamine transport by rat renal brush border membrane vesicles.

Acivicin (L-[alpha S,5S]-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid) reversibly and competitively inhibits glutamine transport in rat renal brush border membrane (BBM) vesicles. Acivicin alters the affinity of the low-Km high-affinity glutamine transport system, but has minimal effect on the high-Km low-affinity system. The drug interferes with glutamine transport by a mechanism that does not involve the maintenance of a Na+-chemical gradient as shown by its uniform effect on glutamine uptake rate, regardless of the NaCl gradient imposed (0 to 150 mmol/L). The effect of acivicin on membrane potential was ruled out by the finding that acivicin modified glutamine transport even when the membrane potential was minimized either by substituting Cl- with an impermeant anion, isethionate, or by short-circuiting the membrane potential with carbonyl cyanide p-trifluoromethoxyphenyl hydrazone. In these experiments the activity of the enzyme gamma-glutamyltranspeptidase (gamma-GT), a component of the putative amino acid transport system, was not suppressed because the BBM was not preincubated with acivicin. Acivicin also interferes with the uptake of other solutes tested (alanine, proline, glutamate, and glucose). But with the exception of L-alanine, the transport of these solutes is less sensitive to the inhibitory effect of acivicin than is that of glutamine. Our results indicate that acivicin profoundly affects the metabolism of renal tubular cells by its influence on the metabolite transport systems. Acivicin can reduce renal NH3 production independently of its effect on gamma-GT by interfering directly with renal cellular uptake of glutamine.