Human cell variants resistant to methylglyoxal-bis(guanylhydrazone) display increased sensitivity to chloramphenicol.

Abstract

Four variants of the cultured human cell line VA2 have been isolated which are resistant to the antiproliferative and antimitochondrial effects of methylglyoxal-bis(guanylhydrazone) (MGBG). Each of the four variants is two- to fivefold more sensitive to the mitochondrial protein synthesis inhibitor chloramphenicol (CAP) than wild type when grown in the absence of MGBG, and five- to tenfold more sensitive to CAP when grown in the presence of MGBG. Uptake studies demonstrate that each MGBG-resistant variant cell line is freely permeable to CAP. The in vivo rates of mitochondrial protein synthesis are significantly reduced in each of the variants whether pregrown and labeled in the presence or absence of MGBG. When cytoplasts from a cytoplasmically inherited CAP-resistant mutant are fused to an MGBG-resistant recipient cell line, cybrid clones can be isolated which are functionally resistant to low levels of CAP. With continued growth, the levels of resistance to CAP do not, however, approach the levels of resistance of the CAP-resistant donor cell line. When CAP resistance is subsequently transferred from a CAP/MGBG-resistant cybrid by enucleation and fusion to other human cell lines, then CAP-resistant cybrids can be readily selected in high levels of CAP. It is possible that the substantial decrease in mitochondrial protein synthesis observed in the variants fully accounts for their increased sensitivity to CAP, although the basis for this decreased rate of mitochondrial protein synthesis is not understood.