Appearance of albumin-producing cells in the liver of analbuminemic rats on aging and administration of mutagens.

Abstract

The lack in serum albumin in analbuminemic rats, a strain derived from Sprague-Dawley rats, was found to be due to deficient synthesis of albumin in the liver caused by a disturbance in the processing of albumin mRNA. The serum albumin gene was cloned from analbuminemic rats and from parental normal Sprague-Dawley rats. Analyses of the nucleotide sequences of these albumin genes revealed that there is a seven base pair deletion in the HI intron of the albumin gene of analbuminemic rats. This deletion extends from the 5th to the 11th base of the 5'-end of the intron causing change in the nucleotide sequence of the 5'-end of the HI intron from GTAGGTT to GTAGCGA. The HI intron sequence was found to be accumulated in the nuclear RNA of analbuminemic rat liver indicating blocking of mRNA splicing. Although analbuminemic rats are almost completely deficient in serum albumin, a small but appreciable amount of "albumin" was detected in their serum. This protein was purified by immunoprecipitation and SDS-gel electrophoresis and shown to have the same immunological crossreactivity and digestion patterns with V8 protease and papain as those of normal rat serum albumin. The concentration of "albumin" increased slightly upon aging of analbuminemic rats. The existence of serum albumin in hepatocytes of analbuminemic rats was studied immunohistochemically by the peroxidase anti-peroxidase method. There were about 1/10(5) albumin-positive cells, presumably albumin-producing hepatocytes at birth, and their number increased gradually to 100 approximately 200/10(4) about 24 months after birth. When the hepatocarcionogenic mutagen 3'-methyl-4-dimethylaminoazobenzene was administered to analbuminemic rats, the number of albumin-positive cells in the liver increased 8-fold in 5 weeks and 10-fold in 15 weeks. A similar increase was observed after administration of acetylaminofluorene, but not after partial hepatectomy or administration of diethylnitrosamine.