Transforming growth factor B1 decreases uptake of glutathione precursor amino acids in bovine pulmonary artery endothelial cells.
We have previously observed that transforming growth factor beta 1 (TGF beta 1) produces a pro-oxidant effect and decreases cellular glutathione (GSH) levels of cultured bovine pulmonary artery endothelial cells (BPAEC) (White A. C., S. K. Das, and B. L. Fanburg. Am. J. Respir. Cell Mol. Biol. 6:364-368, 1992). In the present studies we demonstrate that 2 ng/ml TGF beta 1 reduces the uptake of two GSH precursor amino acids (cystine and glutamate) by 50% (cystine; control 359.35 +/- 100, TGF beta 1 187.7 +/- 26 pmol/10 min/10(6) cells, p < 0.05; glutamate; control 215.15 +/- 18, TGF beta 1 110.2 +/- 16 pmol/10 min/10(6) cells, p < 0.001). The inhibitory effect of TGF beta 1 on the uptake of GSH precursor amino acids persisted in the presence of buthionine sulfoximine (inhibits gamma-glutamyl cysteine synthetase, the rate limiting step in GSH synthesis) or acivicin (inhibits gamma-glutamyl transpeptidase). The uptake of leucine, an amino acid that does not serve as a precursor for GSH, was unaffected by TGF beta 1. In additional experiments TGF beta 1 decreased the levels of cellular and medium GSH-indicating that TGF beta 1 did not increase efflux of GSH from BPAEC. We propose from these observations that TGF beta 1 decreases cellular glutathione, at least in part, through down regulation of precursor amino acid transport and, thereby, its rate of synthesis.
Boustani
M R
MR
Pulmonary and Critical Care Division, New England Medical Center/Tufts University School of Medicine, Boston, MA 02111, USA.
Hertig
I A
IA
Maloney
E K
EK
Fanburg
B L
BL
White
A C
AC
D000818:Animals; D001692:Biological Transport; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002417:Cattle; D002452:Cell Count; D002478:Cells, Cultured; D003553:Cystine / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D018698:Glutamic Acid / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D011651:Pulmonary Artery; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D007555:Isoxazoles; D016212:Transforming Growth Factor beta; D018698:Glutamic Acid; D003553:Cystine; D019328:Buthionine Sulfoximine; D005723:gamma-Glutamyltransferase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; C006303:acivicin