Decrease in the metabolic activating capacities of arylamines in livers bearing hyperplastic nodules: association with the selective changes in hepatic P-450 isozymes.
The mechanism of the alteration in carcinogenic arylamine-activating capacities in livers bearing pre-neoplastic (or hyperplastic) nodules induced by the Solt-Farber protocol was investigated in relation to the changes in hepatic cytochrome P-450 isozymes. In the Salmonella mutagenesis test, the numbers of revertants induced with 2-amino-3-methylimidazo[4,5-f]quinoline and 2-aminofluorene were significantly lower in the presence of microsomes of nodule-bearing livers than of control livers. A similar tendency was also observed with another heterocyclic arylamine, 2-amino-6-methyldipyrido-[1,2-a:3',2'-d]imidazole. In Western blots using specific antibodies against 5 different forms of cytochrome P-450, hepatic contents of P-450-male (a main constitutive form) and P-450b (a main phenobarbital-inducible form) were decreased in the livers with hyperplastic nodules to 63% and 35% of the corresponding controls, while no significant decrease was observed in the contents of P-448-H (a main 3-methylcholanthrene-inducible form), P-450(6 beta-1) (testosterone 6 beta-hydroxylase) and P-450e (a phenobarbital-inducible form). In accordance with the reduction in P-450-male, capacities for microsomal 16 alpha- and 2 alpha-hydroxylations, but not 6 beta-hydroxylation, of testosterone were decreased in the livers with hyperplastic nodules. Although P-448-H has higher capacities for the activation of arylamines than does P-450-male, the hepatic content of P-450-male is more than ten-fold higher than that of P-448-H in both normal and nodule-bearing livers. These results indicate that the selective decrease in hepatic content of P-450-male is likely to be a main cause of the decrease in arylamine metabolic activating capacities in livers with hyperplastic nodules.
Ozawa
S
S
Department of Pharmacology, School of Medicine, Keio University, Tokyo.
Abu-Zeid
M
M
Murayama
N
N
Yamazoe
Y
Y
Kato
R
R
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000378:metabolism; D005449:Fluorenes / Q000493:pharmacokinetics*; D006900:Hydroxylation; D007527:Isoenzymes / Q000378:metabolism*; D008113:Liver Neoplasms / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D011230:Precancerous Conditions / Q000201:enzymology*; D011804:Quinolines / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D013379:Substrate Specificity; D013739:Testosterone / Q000378:metabolism
D002273:Carcinogens; D005449:Fluorenes; D007527:Isoenzymes; D011804:Quinolines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C012177:2-aminofluorene; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D004851:Epoxide Hydrolases