Sulfotransferase-mediated activation of mutagens studied using heterologous expression systems.
Sulfation is a common final step in the biotransformation of xenobiotics and is traditionally associated with inactivation. However, the sulfate group is electron-withdrawing and may be cleaved off heterolytically in some molecules leading to electrophilic cations which may form adducts with DNA and other important cellular structures. Since endogenous sulfotransferases do not appear to be expressed in indicator cells of standard mutagenicity tests, rat and human sulfotransferases have been stably expressed in his- Salmonella typhimurium strain TA1538 and Chinese hamster V79 cells. Using these recombinant indicator cells, sulfotransferase-dependent genotoxic activities were detected with N-hydroxy-2-acetylaminofluorene, 2-acetylaminofluorene (in the presence of co-expressed rat cytochrome P450 1A2), hycanthone, 1'-hydroxysafrole, alpha-hydroxytamoxifen and various benzylic alcohols derived from polycyclic aromatic hydrocarbons. In several cases, it was critical that the reactive sulfuric acid conjugates were formed directly within the indicator cells, owing to the inefficient penetration of cell membranes. In other cases, spontaneous benzylic substitution reactions with medium components, such as halogenide ions or amino acids, led to secondary, membrane-penetrating reactive species. Different sulfotransferases, including related forms from rat and human, substantially differed in their substrate specificity towards the investigated promutagens. It is known that some sulfotransferases are expressed with high tissue and cell type specificities. This site-dependent expression together with the limitations in the distribution of reactive sulfuric acid conjugates may explain organotropic effects of compounds activated by this metabolic pathway.
Glatt
H
H
German Institute of Human Nutrition, Department of Toxicology, Potsdam-Rehbrücke. glatt@www.dife.de
Bartsch
I
I
Christoph
S
S
Coughtrie
M W
MW
Falany
C N
CN
Hagen
M
M
Landsiedel
R
R
Pabel
U
U
Phillips
D H
DH
Seidel
A
A
Yamazoe
Y
Y
D000818:Animals; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics / Q000633:toxicity; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics* / Q000633:toxicity; D011721:Pyrenes / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D012854:Sister Chromatid Exchange / Q000187:drug effects; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism*
D002273:Carcinogens; D009153:Mutagens; D011721:Pyrenes; D001564:Benzo(a)pyrene; C065833:1-hydroxymethylpyrene; D007041:Hypoxanthine Phosphoribosyltransferase; D015238:Sulfotransferases