Abstract
1,3,4-Trimethylpyrrole and 1-methyl-3,4-bis(hydroxymethyl)pyrrole were synthesized and labeled with tritium in the C3 and C4 substituents. Both pyrroles were covalently bound to protein, DNA, and RNA when administered to rats in vivo; the level of binding of the trimethyl compound was an order of magnitude higher than that of the diol in liver. Binding of both pyrroles to protein in vitro was catalyzed by microsomal fractions in the presence of NADPH but not NADH, and the enzymatic activation of the trimethyl compound was inhibited by SKF 525-A, CO, anaerobiosis, or reduced glutathione. The microsomal fractions could be replaced by reconstituted systems containing highly purified NADPH-cytochrome P-450 reductase and cytochrome P-450 in catalyzing the activation of the trimethyl compound. These results indicate that cytochromes P-450 can activate pyrroles to more electrophilic species capable of binding irreversibly to biological macromolecules.
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