REVERSAL OF HYDROQUINONE-MEDIATED SUPPRESSION OF T-CELL PROLIFERATIONBY TRANSFECTION OF THE M2 SUBUNIT OF RIBONUCLEOTIDE REDUCTASE

Hydroquinone (HQ) is a benzene derivative that is found in large quant ities in cigarette tar as a result of the pyrolysis of tobacco flavino ids, HQ is a potent inhibitor of T cell proliferation causing an immed iate and complete cessation of DNA synthesis in IL-2-dependent human T lymphoblasts and Jurkat T cells without loss of cell viability. Previ ous studies from our laboratory demonstrated that the antiproliferativ e effects of HQ could be partially reversed by the addition of deoxyri bonucleosides, but not by the corresponding ribonucleosides, suggestin g that HQ might inhibit ribonucleotide reductase, In the present study , the molecular mechanism behind this observation was further investig ated. Jurkat T cells were stably transfected with a pMEP4 expression v ector containing the gene for the M2 subunit of ribonucleotide reducta se under transcriptional control of the human metallothionein IIA prom oter. M2-transfected Jurkat T cells exhibited a greater than three-fol d increase in resistance to HQ compared to untransfected cells or cell s transfected with the M2 gene in the reverse orientation. HQ resistan ce was associated with an increased level of M2 protein detected by We stern blot, These results suggest that the benzene derivative inhibits lymphocyte proliferation by inhibiting ribonucleotide reductase. (C) 1998 Academic Press.