Bioactivation of N-nitrosopiperidine to mutagens: role of hepatic cytochrome P-450 proteins and contribution of cytosolic fraction.
In the present study the role of two families of cytochrome P-450 proteins and the contribution of the cytosolic fraction in the activation of N-nitrosopiperidine to mutagens in the Ames test were investigated. The bioactivation of this nitrosamine was preferentially catalysed by the phenobarbitone-induced cytochromes P-450, in contrast to the 3-methylcholanthrene-induced cytochromes P-448. The mutagenicity of nitrosopiperidine catalysed by microsomes, in the absence of cytosol, was lower when compared with that observed with S9 fractions. Cytosol itself could not activate nitrosopiperidine but potentiated the microsome-mediated mutagenicity of the carcinogen. The cytosolic potentiation was still evident when microsomal metabolism was terminated, indicating that cytosolic enzyme(s) can further convert the microsome-generated metabolites to more potent mutagens. The cytosolic enzyme(s) was inducible by prior treatment of the rats with phenobarbitone or Arochlor 1254 but not 3-methylcholanthrene. The microsome-mediated activation of nitrosopiperidine could be supported by NADH in the absence of NADPH. It is therefore concluded that the activation of nitrosopiperidine to mutagen(s) involves, in addition to NADH- and NADPH-dependent microsomal enzymes, cytosolic proteins.
Ayrton
A D
AD
Department of Biochemistry, University of Surrey, Guildford, UK.
Smith
J N
JN
Ioannides
C
C
D000818:Animals; D001711:Biotransformation; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D003580:Cytochromes / Q000502:physiology; D003600:Cytosol / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009153:Mutagens / Q000378:metabolism*; D009243:NAD / Q000494:pharmacology; D009602:Nitrosamines / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains
D003580:Cytochromes; D009153:Mutagens; D009602:Nitrosamines; D009243:NAD; C002743:N-nitrosopiperidine; D003577:Cytochrome P-450 Enzyme System; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2