Effects of hepatocarcinogenic initiators on aldehyde dehydrogenase gene expression in cultured rat hepatic cells.
The effects of certain in vivo inducers of tumor-associated aldehyde dehydrogenase (aldehyde:NAD+ oxidoreductase, EC 1.2.1.3; ALDH) activity on the expression of tumor-associated ALDH (T-ALDH) in vitro have been investigated using cultured rat hepatocytes and hepatoma cell lines. Two distinct groups of T-ALDH inducers have been identified. Three hepatocarcinogenic initiators 2-acetylaminofluorene, diethylnitrosamine and ethionine, which cause changes in T-ALDH in vivo, do not induce T-ALDH activity in cultured rat hepatocytes or hepatoma cell lines following either short-term or long-term exposures. In contrast, polycyclic aromatic hydrocarbons, such as 3-methylcholanthrene, benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene, induce an immediate increase of T-ALDH activity in both cultured rat hepatocytes and hepatoma cell lines. Synthesis and degradation rates of T-ALDH mRNA and protein have also been determined. The synthesis of T-ALDH protein is coupled with the increased synthesis of T-ALDH mRNA when the T-ALDH gene is constitutively expressed or activated by an inducer. Both T-ALDH mRNA (t1/2 = 25 - 34 h) and protein (t1/2 = 88 - 95 h) in high T-ALDH activity cell lines or low-activity cell lines treated with an inducer are relatively stable. Combined with previous studies, the results suggest that at least two different mechanisms are involved in T-ALDH gene expression; events occurring during initiation as well as during promotion appear to be involved in the genetically stable changes in T-ALDH gene expression which occur in vivo. The results also indicate that the lack of T-ALDH activity in normal hepatocytes or low-activity hepatoma cell lines is due to repression of the T-ALDH gene rather than to the differential stability of T-ALDH mRNA or protein.
Huang
M
M
Department of Biochemistry and Molecular Biology, University of South Dakota, School of Medicine, Vermillion 57069.
Lindahl
R
R
D015073:2-Acetylaminofluorene; D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D004052:Diethylnitrosamine; D004790:Enzyme Induction / Q000187:drug effects; D005001:Ethionine; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics*; D008748:Methylcholanthrene; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D051381:Rats; D014407:Tumor Cells, Cultured / Q000201:enzymology
D012333:RNA, Messenger; D012334:RNA, Neoplasm; D004052:Diethylnitrosamine; D008748:Methylcholanthrene; D015073:2-Acetylaminofluorene; D000444:Aldehyde Dehydrogenase; D005001:Ethionine