Murine alpha/beta interferons inhibit benzo(a)pyrene activation and mutagenesis in mice.
In addition to their antiviral and immune regulatory properties, interferons (IFNs) are known to depress hepatic cytochrome P450-dependent metabolism. As many chemical mutagens and carcinogens require bioactivation by the mixed-function monooxygenase (MFO) system in order to be genotoxic, a combined genetic and biochemical approach was used to establish whether IFNs could inhibit the activation of benzo(a)pyrene (BaP) to the ultimate clastogenic metabolite(s) in vivo. Treatment of mice with murine IFN-alpha/beta depressed cytochrome P450 content, as well as ethoxyresorufin O-deethylase activity (EROD), as a probe of class IA1 P450 isozymes, for 24 hrs and delayed the attainment of normal levels to approximately 30 hrs. After IFNs plus BaP treatment, EROD activity showed a reduction up to 70% after 24 hrs with an enhancement in activity at 30 hrs. A positive correlation exists between the rate of inhibition of oxidative BaP hepatic metabolism and inhibition of clastogenic effects in vivo, as scored in the bone marrow chromosome aberration assay.
Hrelia
P
P
Department of Pharmacology, University of Bologna, Italy.
Morotti
M
M
Vigagni
F
F
Maffei
F
F
Paolini
M
M
Forti
G C
GC
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000378:metabolism* / Q000633:toxicity*; D001711:Biotransformation; D001853:Bone Marrow / Q000187:drug effects; D002869:Chromosome Aberrations; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007370:Interferon Type I / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism
D016588:Anticarcinogenic Agents; D007370:Interferon Type I; D001564:Benzo(a)pyrene; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1