DECREASED EXPRESSION OF GAMMA-GLUTAMYL-TRANSPEPTIDASE IN THE INTESTINAL-CELL LINE CACO-2 BY INDUCERS OF CYTOCHROME-P450 1A1

Our purpose was to investigate whether inducers of cytochrome P450 1A1 (CYP1A1), which cause a decreased expression in Caco-2 cells, at both the mRNA and protein levels, of membrane proteins associated with the uptake and transport of hexoses, would also affect the expression of gamma-glutamyltranspeptidase (gamma GT) (EC 2.3.2.2). In Caco-2 clonal TC7 cells grown under standard conditions (25 mM glucose), exposure t o beta-naphthoflavone (beta-NF), 2, 3, 7, 8-tetrachlorodibenzo-p-dioxi n, and 3-methylcholanthrene resulted in increased glucose consumption and decreased gamma GT activity in cells grown to confluence, i.e. whe n the differentiation is optimum, gamma GT activity was further analyz ed during the time course of differentiation of TC7 cells treated or n ot with beta-naphthoflavone: while gamma GT activity in untreated cell s showed a 10-fold increase from the exponential phase of growth until late postconfluence, gamma GT activity in beta-NF-treated cells, alth ough increasing by 4-fold, remained at a much lower level (<25%). This decreased activity of gamma GT was associated with a decreased level of gamma GT mRNA. This inhibiting effect was not dependent on the CYP1 A1 activity, as it also occurred in the presence of CYP1A1 inhibitors such as alpha-naphthoflavone, 8-methoxypsoralen or ellipticin. It was however dependent on glucose supply as it was not observed when the ce lls were cultured in low glucose (1 mM). These results raise the quest ion of whether, in Caco-2 cells, CYP1A1 inducers or the signal transdu ction system which controls CYP1A1 are involved in the regulation of t he expression of gamma GT through a mechanism involving glucose metabo lism. BIOCHEM PHARMACOL 56;7:817-823, 1998. (C) 1998 Elsevier Science Inc.