Genetic basis for lithium toxicity and its relationship with tissue distribution: a diallel cross analysis of six strains of mice.
Lithium toxicity measured as the time to death following an intraperitoneal injection of a lethal dose (900 mg/kg) of lithium chloride was determined in 8-week-old males from six genetic strains of mice (Balb/c, C3H/S, C57BL/6J, DBA/2, 129/ReJ, and S.W.) and their F1 hybrids. These genotypes were also evaluated for the Li+ distribution in the body 1 h after an i.p. injection of a 200 mg/kg dose of LiCl. Genotype differences in toxicity and lithium concentration in eight tissues, excreta, and urine were all statistically significant. Significant rank correlation with toxicity was found for Li+ levels in three of the tissues (kidney, lung, and blood), excreta, and urine. Diallel cross analysis was used to investigate the genetic properties of the mouse strains in responding to the toxic effects of lithium and in regulating its levels in these tissues, excreta, and urine. Our results suggest that genetically influenced membrane transport which regulates the elimination of the ion via urine and feces is an essential component in determining lithium toxicity. In general, there was a high degree of intra- and inter-genic interaction among genetic determinants of toxicity and its distribution in a number of tissues. The order of dominance of the strains as determined by (Vr, Wr) graph was different for each of the systems analysed. It is realized that the Li+ distribution in the different parts of the body is not the only factor affecting lithium toxicity.
D000483:Alleles; D000818:Animals; D002712:Chlorides / Q000633:toxicity*; D003433:Crosses, Genetic; D005838:Genotype; D008094:Lithium / Q000633:toxicity*; D018021:Lithium Chloride; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C / Q000235:genetics; D008809:Mice, Inbred C3H / Q000235:genetics; D008810:Mice, Inbred C57BL / Q000235:genetics; D008811:Mice, Inbred DBA / Q000235:genetics; D008815:Mice, Inbred Strains / Q000235:genetics*; D013045:Species Specificity; D014018:Tissue Distribution
D002712:Chlorides; D008094:Lithium; D018021:Lithium Chloride