Human phenol sulfotransferases hP-PST and hM-PST activate propane 2-nitronate to a genotoxicant.
The industrial solvent 2-nitropropane (2-NP) is a genotoxic hepatocarcinogen in rats. The genotoxicity of the compound in rats has been attributed to sulfotransferase-mediated formation of DNA-reactive nitrenium ions from the anionic form of 2-NP, propane 2-nitronate (P2N). Whether human sulfotransferases are capable of activating P2N is unknown. In the present study we have addressed this question by investigating the genotoxicity of P2N in various V79-derived cell lines engineered for expression of individual forms of human sulfotransferases, the phenol-sulfating and the monoamine-sulfating phenol sulfotransferases (hP-PST and hM-PST) and the human hydroxysteroid sulfotransferase (hHST). Genotoxicity was assessed by measuring the induction of DNA repair synthesis and by analyzing the formation of DNA modifications. P2N induced repair synthesis in V79-hP-PST and V79-hM-PST cells, whereas induction of repair synthesis in V79-hHST cells was negligible. P2N also resulted in the formation of 8-aminodeoxyguanosine and increased the level of 8-oxodeoxyguanosine in V79-hP-PST cells, but not in the parental V79-MZ cells, which do not show any sulfotransferase activity. Acetone oxime, the tautomeric form of the first reduction product of 2-NP, 2-nitrosopropane, was inactive in all cell lines. The results show that the human phenol sulfotransferases P-PST and M-PST are capable of metabolically activating P2N (P-PST >> M-PST) and that the underlying mechanism is apparently identical to that resulting in the activation of P2N in rat liver, where 2-NP causes carcinomas. These results support the notion that 2-NP should be regarded as a potential human carcinogen.
Kreis
P
P
GSF-National Research Center for Environment and Health, Institute of Toxicology, D-85764 Neuherberg, Germany.
Brandner
S
S
Coughtrie
M W
MW
Pabel
U
U
Meinl
W
W
Glatt
H
H
Andrae
U
U
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D015239:Arylsulfotransferase; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018736:DNA Adducts; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D006801:Humans; D008168:Lung / Q000166:cytology; D009152:Mutagenicity Tests; D009595:Nitroparaffins / Q000378:metabolism* / Q000493:pharmacokinetics*; D010091:Oximes / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics*; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015238:Sulfotransferases / Q000378:metabolism*
C117878:8-amino-2'-deoxyguanosine; D002273:Carcinogens; D018736:DNA Adducts; D009595:Nitroparaffins; D010091:Oximes; D011355:Prodrugs; D011993:Recombinant Fusion Proteins; C069720:propane-2-nitronate; D000080242:8-Hydroxy-2'-Deoxyguanosine; D015238:Sulfotransferases; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C403170:monoamine-sulfating phenol sulfotransferase; C028152:alcohol sulfotransferase; D003849:Deoxyguanosine; C016617:2-nitropropane; C035911:acetoxime; D011407:Propane