1-Hydroxymethylpyrene and its sulfuric acid ester: toxicological effects in vitro and in vivo, and metabolic aspects.
1-Hydroxymethylpyrene (HMP) is activated to a potent mutagen, detectable in Salmonella typhimurium, in the presence of hepatic cytosol, cofactor for sulfotransferases, and chloride anions. The number of induced mutations is linear to the amount of cytosol used over a wide range, allowing for the quantification of this activity. The activity is expressed with high selectivity in certain tissues and cell types. In adult rats, the highest level is found in the liver, the activity in females exceeding that in males about threefold. About half of the activity in the liver of females is provided by hydroxysteroid sulfotransferase a (STa), whereas other enzymes may be more important in males on account of their very low level of STa. The expression of STa is decreased in ATPase-negative, presumably preneoplastic, hepatic foci in female rats. In contrast to its high mutagenicity in bacteria, SMP shows only weak mutagenic activity in mammalian cells (Chinese hamster V79 cells), independently of whether it is externally added, or generated from HMP within the cells by heterologously expressed STa. Sulfation, however, strongly enhances the cytotoxicity of HMP in mammalian cells. The high cytotoxicity and low mutagenicity in mammalian cells in culture have possible correlates in vivo: while HMP is only a weak initiator of ATPase-negative hepatic foci in newborn rats, it shows substantial promoting activity with regard to such foci in female, but not in male rats. We postulate that this promotion results from selective toxification by STa in the normal hepatic parenchyma of female rats, and resistance of ATPase/STa-negative foci.
Department of Toxicology, German Institute of Human Nutrition, Potsdam-Rehbrücke.
H
H
Glatt
G
G
Werle-Schneider
N
N
Enders
S
S
Monnerjahn
J
J
Pudil
A
A
Czich
A
A
Seidel
M
M
Schwarz
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004952:Esters / Q000378:metabolism / Q000633:toxicity; D005260:Female; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D011721:Pyrenes / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D015238:Sulfotransferases / Q000378:metabolism*; D013464:Sulfuric Acids / Q000378:metabolism
D004952:Esters; D009153:Mutagens; D011721:Pyrenes; D013464:Sulfuric Acids; D004247:DNA; C065833:1-hydroxymethylpyrene; D015238:Sulfotransferases; C028152:alcohol sulfotransferase; D000251:Adenosine Triphosphatases; C033158:sulfuric acid