Abstract
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 resistancein vivo. We characterized the acute and tissue-specific toxicity of hygromycin B in transgenic mice bearing the hygromycin B phosphotransferase (hygR ) gene under control of a constitutive promoter. We characterized the tissue-specific expression of hygR mRNA and also investigated the acute toxicity of hygromycin B in hygR and wild-type mice. The hygR 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 hygR 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 hygR 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 inhygR mice. Our results show that constitutive expression of the bacterial hygR gene in transgenic mice in vivo confers resistance to hygromycin B.
Footnotes
-
Send reprint requests to: Robert H. Schiestl, Department of Molecular and Cellular Toxicology, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115.
-
↵1 This work was supported by grant No. 1RO1ES07694 from the National Institutes of Health to R.H.S., grant No. MCB-9513537 from the National Science Foundation to E.M.S. and NIH Cancer Core Grant CA34196 at Jackson Laboratory.
-
↵2 Department of Veterinary Pathology, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.
-
↵3 The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609.
- Abbreviations:
- ALT
- alanine aminotransferase
- AST
- aspartate aminotransferase
- BUN
- blood urea nitrogen
- ESC
- embryonic stem cells
- hygR
- hygromycin B phosphotransferase
- IOD
- integrated optical density
- LD50
- median lethal dose
- Received August 12, 1996.
- Accepted January 22, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|