EXPRESSION OF HYG(R) IN TRANSGENIC MICE CAUSES RESISTANCE TO TOXIC EFFECTS OF HYGROMYCIN-B IN-VIVO

Aminoglycoside antibiotics are indispensable for treatment of serious bacterial infections, and despite careful attention to dosage regimens , nephrotoxicity and ototoxicity still cause concern. In the present s tudy, we tested whether side effects of aminoglycoside therapy could b e limited by expression of prokaryotic genes of antibiotic resistance in vivo. We characterized the acute and tissue-specific toxicity of hy gromycin B in transgenic mice bearing the hygromycin B phosphotransfer ase (hyg(R)) gene under control of a constitutive promoter. We charact erized the tissue-specific expression of hyg(R) mRNA and also investig ated the acute toxicity of hygromycin B in hyg(R) and wild-type mice. The hyg(R) mRNA reached its highest levels in brain and reached interm ediate levels in spleen, muscle, kidney, liver and testis. The lowest levels were detected in heart and lungs. The hyg(R) expression in tran sgenic animals caused an 89-fold increase in the approximate lethal do se of hygromycin B compared with wild-type mice. Serum biochemical ana lysis of hyg(R) and wild-type mice treated with lethal doses of hygram ycin B indicated liver and kidney damage measured as ALT, AST and BUN. On the morphological level, these changes led to acute tubular nephro sis in wild-type mice and acute liver damage in hyg(R) mice. Our resul ts show that constitutive expression of the bacterial hyg(R) gene in t ransgenic mice in vivo confers resistance to hygromycin B.