Induction of the P-450 I family of proteins by polycyclic aromatic hydrocarbons: possible relationship to their carcinogenicity.
The hypothesis has been put forward that mutagenic polycyclic aromatic hydrocarbons which induce the P-450 I family of cytochromes, the major enzyme system responsible for their activation, are likely to be carcinogenic. In order to test this hypothesis, rats have been pretreated with a number of polycyclic aromatic hydrocarbons of different mutagenic and carcinogenic potency and hepatic P-450 I activity was monitored using chemical probes such as the O-deethylation of ethoxyresorufin and metabolic activation of Glu-P-1 to mutagens, and immunologically employing polyclonal antibodies against purified rat P-450 I A1. All compounds studied enhanced P-450 I activity and induced P-450 I apoproteins but the extent of induction was very markedly different. The results are discussed with reference to the mutagenicity of these chemicals in the Ames test and their carcinogenicity in the classical mouse skin model. A relationship appears to exist between carcinogenicity of polycyclic aromatic hydrocarbons and their ability to induce hepatic P-450 I activity.
Ayrton
A D
AD
Department of Biochemistry, University of Surrey, Guildford, U.K.
McFarlane
M
M
Walker
R
R
Neville
S
S
Coombs
M M
MM
Ioannides
C
C
D000818:Animals; D001564:Benzo(a)pyrene / Q000494:pharmacology; D001580:Benzopyrenes / Q000494:pharmacology; D001711:Biotransformation; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000494:pharmacology*; D002911:Chrysenes / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D006067:Gonanes / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009152:Mutagenicity Tests; D011083:Polycyclic Compounds / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D001580:Benzopyrenes; D002273:Carcinogens; D002911:Chrysenes; D006067:Gonanes; D011083:Polycyclic Compounds; D001564:Benzo(a)pyrene; C026487:benzo(e)pyrene; C005765:15,16-dihydro-11-methylcyclopenta(a)phenanthren-17-one; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases