PMID- 8565141
OWN - NLM
STAT- MEDLINE
DCOM- 19960301
LR  - 20190512
IS  - 0143-3334 (Print)
IS  - 0143-3334 (Linking)
VI  - 17
IP  - 1
DP  - 1996 Jan
TI  - The model Ah-receptor agonist beta-naphthoflavone inhibits aflatoxin B1-DNA 
      binding in vivo in rainbow trout at dietary levels that do not induce CYP1A 
      enzymes.
PG  - 79-87
AB  - beta-Naphthoflavone (BNF), a well-known Ah-receptor agonist, has been believed to 
      inhibit aflatoxin B1 (AFB1) carcinogenesis in rats and rainbow trout primarily 
      through induction of the cytochrome P450 1A (CYP1A) enzyme subfamily and 
      consequent diversion of AFB1 to the less carcinogenic phase I metabolite 
      aflatoxin M1 (AFM1). This study investigates the dose responsive effects of 
      dietary BNF treatment on CYP1A induction. AFM1 formation, AFB1-8,9-epoxide 
      formation and AFB1-DNA binding in the trout model. Pre-feeding diet containing 
      10-200 p.p.m. BNF after AFB1 i.p. injection provided dose-dependent induction of 
      CYP1A-dependent ethoxyresorufin-O-deethylase (EROD) activity and inhibition of in 
      vivo AFB1-DNA binding. However, most of the observable inhibition of DNA 
      adduction (45% inhibition) had occurred at 10 p.p.m. BNF without detectable EROD 
      induction; higher doses of BNF up to 200 p.p.m. induced EROD > 6-fold but 
      provided only another 15% inhibition of DNA adduction in vivo. When in vitro 
      AFB1-DNA binding was assessed using liver microsomes from trout fed 10-100 p.p.m. 
      BNF, induced microsomal EROD activity correlated moderately with reduction of in 
      vitro AFB1-DNA binding activity. However, BNF treatment in a low dose range 
      (0.2-10 p.p.m.) also strongly inhibited in vivo hepatic AFB1-DNA binding (69% 
      inhibition at 5 p.p.m. BNF in this experiment), in a dose-dependent manner, in 
      the complete absence of detectable EROD induction. The microsomes from 5 p.p.m. 
      BNF-treated trout had no more EROD activity than control microsomes, and no less 
      capacity for catalyzing AFB1-DNA binding in vitro than control microsomes. Thus, 
      the potent inhibition of hepatic AFB1-DNA binding in vivo by 5 p.p.m. BNF was a 
      result of neither CYP1A enzyme induction nor irreversibly reduced catalytic 
      capacity for AFB1-8,9-epoxide formation. Direct analysis of AFB1 metabolites 
      formed in vitro by liver microsomes from trout fed 10, 100 and 500 p.p.m. BNF 
      showed that low dietary BNF (10 p.p.m.) neither induced microsomal CYP1A-mediated 
      AFM1 formation nor altered AFB1-8,9-epoxide formation compared to the control. By 
      comparison, 100 and 500 p.p.m. BNF pretreatment significantly elevated 
      microsome-catalyzed AFM1 formation in vitro (P < 0.001), and this increase was 
      highly correlated with increased EROD activity (r2 = 0.999, P < 0.001). Upon in 
      vitro addition, BNF was found to be a potent inhibitor of microsome-mediated 
      AFB1-8,9-exo-epoxide formation (IC50 = 2.6 +/- 0.1 microM) and AFB1-DNA binding 
      (inhibition constant Ki = 3.03 +/- 0.25 microM). These findings indicate that 
      CYP1A enzyme induction can contribute modestly to BNF protection against AFB1 in 
      this species both in vivo and in vitro at higher BNF doses, but does not do so at 
      lower doses. Instead, enzyme inhibition by BNF against AFB1 8,9-epoxidation 
      appears to be the predominant protective mechanism at higher BNF doses, and the 
      sole protective mechanism at low doses, in the rainbow trout. These findings 
      demonstrate that mechanisms of chemoprevention can change with anticarcinogen 
      dose, and caution that even potent induction of phase I or phase II activities 
      does not assure that pathway to be a predominant protective mechanism in vivo.
FAU - Takahashi, N
AU  - Takahashi N
AD  - Department of Food Science and Technology, Oregon State University, Corvallis 
      97331, USA.
FAU - Harttig, U
AU  - Harttig U
FAU - Williams, D E
AU  - Williams DE
FAU - Bailey, G S
AU  - Bailey GS
LA  - eng
GR  - CA34732/CA/NCI NIH HHS/United States
GR  - ES03850/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (Anticarcinogenic Agents)
RN  - 0 (Benzoflavones)
RN  - 0 (DNA Adducts)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 0 (aflatoxin B1-DNA adduct)
RN  - 6051-87-2 (beta-Naphthoflavone)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - 9N2N2Y55MH (Aflatoxin B1)
RN  - EC 1.- (Oxidoreductases)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
SB  - IM
MH  - Aflatoxin B1/*metabolism
MH  - Animals
MH  - Anticarcinogenic Agents/*pharmacology
MH  - Benzoflavones/*pharmacology
MH  - Cytochrome P-450 CYP1A1
MH  - Cytochrome P-450 Enzyme System/*biosynthesis
MH  - DNA Adducts/*metabolism
MH  - Diet
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Induction/drug effects
MH  - Oncorhynchus mykiss
MH  - Oxidoreductases/*biosynthesis
MH  - Receptors, Aryl Hydrocarbon/*agonists
MH  - beta-Naphthoflavone
EDAT- 1996/01/01 00:00
MHDA- 1996/01/01 00:01
CRDT- 1996/01/01 00:00
PHST- 1996/01/01 00:00 [pubmed]
PHST- 1996/01/01 00:01 [medline]
PHST- 1996/01/01 00:00 [entrez]
AID - 10.1093/carcin/17.1.79 [doi]
PST - ppublish
SO  - Carcinogenesis. 1996 Jan;17(1):79-87. doi: 10.1093/carcin/17.1.79.