Enhancement by cysteinyl thiols of acetyltransferase-mediated, but not of sulfotransferase-mediated, binding of a pyrolysate-derived N-hydroxyarylamine, 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole, to DNA.
The effect of thiols on the activation of a pyrolysate-derived N-hydroxyarylamine, 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole (N-hydroxy-Glu-P-1), was studied in vitro. In hepatic cytosol of rats, [3H]-N-hydroxy-Glu-P-1 bound covalently to calf thymus DNA in the presence of acetyl CoA or 3'-phosphoadenosine-5'-phosphosulfate (PAPS). The extent of the binding of N-hydroxy-Glu-P-1 in a PAPS-dependent system was decreased by the addition of 10 mM glutathione, N-acetyl-L-cysteine, 2-mercaptoethanol or dithiothreitol. However, acetyl CoA-dependent binding of N-hydroxy-Glu-P-1 was stimulated by the addition of 10 mM N-acetyl-L-cysteine (3 fold), L-cysteine (2 fold) or glutathione (1.2 fold), but not 10 mM 2-mercaptoethanol or L-methionine. After hydrolysis of the modified DNA, no difference was detected in the physicochemical properties of the nucleoside adduct formed in the acetyl CoA-supported system with and without thiols. These results indicate that thiols with a cysteine residue are able to affect the activation of carcinogenic heterocyclic arylamines selectively by the modulation of the acetyltransferase-mediated, but not the sulfotransferase-mediated, pathway.
Abu-Zeid
M
M
Department of Pharmacology, School of Medicine, Keio University, Tokyo.
Staiano
N
N
Yamazoe
Y
Y
Kato
R
R
D000105:Acetyl Coenzyme A / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D000123:Acetyltransferases / Q000494:pharmacology*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D004229:Dithiothreitol / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D007093:Imidazoles / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology; D008623:Mercaptoethanol / Q000494:pharmacology; D008715:Methionine / Q000494:pharmacology; D010724:Phosphoadenosine Phosphosulfate / Q000494:pharmacology; D051381:Rats; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D015238:Sulfotransferases / Q000494:pharmacology*
D007093:Imidazoles; D013438:Sulfhydryl Compounds; D010724:Phosphoadenosine Phosphosulfate; D008623:Mercaptoethanol; D000105:Acetyl Coenzyme A; C023786:2-hydroxyamino-6-methyldipyrido(1,2-a-3',2'-d)imidazole; D004247:DNA; D008715:Methionine; D000123:Acetyltransferases; D015238:Sulfotransferases; D005978:Glutathione; D003545:Cysteine; D004229:Dithiothreitol; D000111:Acetylcysteine