Activation of promutagens by endogenous and heterologous sulfotransferases expressed in continuous cell cultures.
Various environmental chemicals are metabolised to chemically reactive sulfuric acid esters, which may covalently bind to cellular macromolecules and induce mutations and tumours. This activation pathway is usually not taken into account in external xenobiotic-metabolising systems used in short-term tests. We therefore analysed the abilities of cytosols from mammalian cell lines to activate benzylic alcohols (1-hydroxymethylpyrene and 9-hydroxymethylanthracene) to mutagens detectable in Salmonella typhimurium TA98. No activation was observed in cell lines which are commonly used in mutagenicity and cell transformation assays, and only low activities were found in epithelial cell lines in culture. We have therefore constructed Chinese hamster V79-derived cell lines which stably express a heterologous sulfotransferase, rat hydroxysteroid sulfotransferase a. Cytosol of these cells effectively activated 1-hydroxymethylpyrene and 9-hydroxymethylanthracene to mutagens detected in S. typhimurium. The hepatocarcinogen 6-hydroxymethylbenzo[a]pyrene induced gene mutations in sulfotransferase-expressing V79-derived cells, whereas it elicited only marginal effects in sulfotransferase-deficient control cells. The new cell lines may allow the detection of novel classes of mutagens, since some externally generated reactive sulfuric acid esters may not readily penetrate target cells due to their short life span and their ionization.
Glatt
H
H
Department of Toxicology, University of Mainz, Germany.
Pauly
K
K
Piée-Staffa
A
A
Seidel
A
A
Hornhardt
S
S
Czich
A
A
D000818:Animals; D000873:Anthracenes / Q000493:pharmacokinetics / Q000633:toxicity; D001592:Benzyl Alcohols / Q000493:pharmacokinetics* / Q000633:toxicity; D001711:Biotransformation; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics* / Q000633:toxicity; D011355:Prodrugs / Q000493:pharmacokinetics*; D011721:Pyrenes / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*
D000873:Anthracenes; D001592:Benzyl Alcohols; D009153:Mutagens; D011355:Prodrugs; D011721:Pyrenes; C049587:9-hydroxymethylanthracene; C065833:1-hydroxymethylpyrene; D015238:Sulfotransferases