Vol. 281, Issue 2, 992-997, 1997

Expression of hyg^R in Transgenic Mice Causes Resistance to Toxic Effects of Hygromycin B In Vivo¹

Jiri Aubrecht, Mary E. P. Goad², Elizabeth M. Simpson³ and Robert H. Schiestl

Department of Molecular and Cellular Toxicology, Harvard School of Public Health, 665 Huntington Ave., Boston, Massachusetts

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 study, we tested whether side effects of aminoglycoside therapy could be limited by expression of prokaryotic genes of antibiotic resistance in vivo. We characterized the acute and tissue-specific toxicity of hygromycin B in transgenic mice bearing the hygromycin B phosphotransferase (hyg^R) gene under control of a constitutive promoter. We characterized the tissue-specific expression of hyg^R mRNA and also investigated 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 intermediate levels in spleen, muscle, kidney, liver and testis. The lowest levels were detected in heart and lungs. The hyg^R expression in transgenic animals caused an 89-fold increase in the approximate lethal dose of hygromycin B compared with wild-type mice. Serum biochemical analysis of hyg^R and wild-type mice treated with lethal doses of hygromycin B indicated liver and kidney damage measured as ALT, AST and BUN. On the morphological level, these changes led to acute tubular nephrosis in wild-type mice and acute liver damage in hyg^R mice. Our results show that constitutive expression of the bacterial hyg^R gene in transgenic mice in vivo confers resistance to hygromycin B.