Increased mutagenicity of 1,2-dibromo-3-chloropropane and tris(2,3-dibromopropyl)phosphate in Salmonella TA100 expressing human glutathione S-transferases.
We have expressed human glutathione S-transferases GSTA1-1 and GSTP1-1 in Salmonella typhimurium TA100 in order to assess the ability of these enzymes to modulate the mutagenicity of 1,2-dibromo-3-chloropropane (DBCP) and tris(2,3-dibromopropyl)phosphate (Tris-BP). Both compounds were mutagenic when activated by Aroclor-induced rat liver microsomes. However, when Aroclor-induced rat liver microsomes were used together with the GST-expressing strains the mutagenicity of both DBCP and Tris-BP was markedly potentiated. Neither of the GST-expressing strains potentiated the mutagenicity in the absence of microsomes, indicating that cytochrome P450-mediated metabolism was a prerequisite for GST-mediated potentiation. With DBCP both isozymes had comparable effects on mutagenic frequency, although the highest dose of DBCP was toxic in strains expressing GSTP1-1. In the case of Tris-BP, GSTP1-1 was much more active in potentiating the mutagenicity. These results indicate that human GSTs can play an important role in the activation of compounds such as DBCP and Tris-BP to mutagenic metabolites.
Simula
T P
TP
Molecular Pharmacology Unit, Biomedical Research Centre, Ninewells Hospital, Dundee, UK.
Glancey
M J
MJ
Söderlund
E J
EJ
Dybing
E
E
Wolf
C R
CR
D000818:Animals; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D005411:Flame Retardants / Q000633:toxicity; D015870:Gene Expression; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007306:Insecticides / Q000633:toxicity; D008862:Microsomes, Liver / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D010755:Organophosphates / Q000633:toxicity*; D011407:Propane / Q000031:analogs & derivatives* / Q000633:toxicity; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000201:enzymology
D005411:Flame Retardants; D007306:Insecticides; D009153:Mutagens; D010755:Organophosphates; D011994:Recombinant Proteins; C012085:tris(2,3-dibromopropyl)phosphate; C007318:1,2-dibromo-3-chloropropane; D005982:Glutathione Transferase; D011407:Propane