We examined whether survival of different rat strains administered anthrax lethal toxin is genetically determined. A reproducible test population of first filial generation hybrid rats was bred based on the susceptibility of progenitors to anthrax lethal toxin and to maximize genetic diversity across the strains. These rats were then tested with varying doses of anthrax lethal toxin. We found that all 'sensitive' strains died within 2 h following systemic administration of 240 mg/kg lethal toxin, while one strain survived following a five times higher dose (1.4 mg/kg). The ability of lethal toxin to lyse macrophage cultures derived from the bone marrow of these strains corresponded with in vivo results. We conclude that a rat test population can detect strain differences in response to anthrax lethal toxin. Survival is influenced by the host genome background and is likely due to a single gene with a recessive mode of inheritance.
BACKGROUND/AIMS
Over 90% of drug candidates fail in clinical trials, incurring high costs to the pharmaceutical industry. To address this problem, PhysioGenix has developed a novel combinatorial breeding strategy, the PharmGenix™ panel, to capture greater genetic diversity within the rat genome and allow for preclinical drug screening. Tacrine, which causes hepatotoxicity in a small percentage of the human population, was tested to demonstrate the utility of this panel.
METHODS
A single dose of tacrine (35 mg/kg) was administered to each of six hybrid PharmGenix™ strains, CD‐IGS and CDF strains. Rats were euthanized twenty‐four hours later and serum analyzed for alanine transaminase (ALT) and aspartate transaminase (AST) levels, indicators of hepatotoxicity.
RESULTS
Tacrine did not significantly elevate ALT levels in CD‐IGS or CDF, however, the PharmGenix™ panel showed significant ALT elevations in five of the six strains, ranging from 111% to 142% of control values. CD‐IGS and CDF exhibited increases in AST levels of 82% and 174%, respectively, while the PharmGenix ™ rats showed much higher AST levels, ranging between 621% and 1069% of control values in four of the six strains.
CONCLUSIONS
The ability to detect significant AST and ALT elevations in the PharmGenix™ panel, but not in CD‐IGS or CDF, suggests a genetic component underlies the development of tacrine toxicity and may have alerted the pharmaceutical industry to toxicity currently seen in a small percentage of the human population.
Clinical Pharmacology & Therapeutics (2005) 79, P82–P82; doi:
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.