In this review, we have examined the biochemical and toxic responses produced by halogenated aromatic hydrocarbons and have tried to develop a model for their mechanism of action. These compounds bind to a cellular receptor and evoke a sustained pleiotropic response. In many tissues this response consists of the expression of a battery of enzymes which are, for the most part, involved in drug metabolism, but in other tissues, those which develop toxicity, an additional set of genes is expressed which effects cellular involution, division, and/or differentiation. The toxicity of these compounds appears to be due to the sustained expression of a normal cellular regulatory system, of which we were previously unaware. In future investigations it is hoped that we will learn the nature and physiologic role of this regulatory system. Only then can we hope to understand the mechanism of toxicity of these compounds.

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The efficient immortalization of primary resting human B lymphocytes by Epstein-Barr virus (EBV) requires several viral genes and presumably the altered expression of an unknown number of cellular genes as well. In this paper, I show that infection of primary human B cells with EBV increased the transcript level of the proto-oncogene, c-fgr, 10-fold. This effect on the level of c-fgr transcripts in B cells was not secondary to blast formation, because levels of c-fgr RNA were also increased 10-fold in two proliferating EBV-negative Burkitt's lymphoma-derived cell lines, Ramos and BJAB, 2 days after infection with EBV. Two lines of evidence indicated that EBV nuclear antigen 2 (EBNA-2) mediates this increase in c-fgr RNA levels: acute infection of BJAB and Ramos cells by a mutant strain of EBV that lacked the EBNA-2 open reading frame, P3HR1, did not affect c-fgr RNA levels; and cell lines constitutively expressing only the EBNA-2 gene of EBV had increased levels of c-fgr RNA relative to those in the parental cell lines. Since P3HR1, a nonimmortalizing strain of EBV, failed to affect c-fgr RNA levels and since a viral gene required for B-cell immortalization was responsible for the induction of c-fgr, the data indicate a possible role of c-fgr expression in B-lymphocyte immortalization by EBV and a mechanism by which EBNA-2 contributes to the immortalizing activity of EBV.

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