Butylated hydroxyanisole-induced alterations in cell kinetic parameters in rat forestomach in relation to its oxidative cytochrome P-450-mediated metabolism.
Four groups of six male Wistar rats (85 +/- 7 g) were fed a diet containing 0% (control) or 2% of the carcinogenic food antioxidant butylated hydroxyanisole (BHA) for 2 weeks. In this experiment, feeding 2% BHA is equivalent to a dose of 2.1 +/- 0.3 g BHA/kg/day. One 0% BHA and one 2% BHA-fed group of rats were daily injected i.p. with the cytochrome P-450 inducer phenobarbital (PB; 60 mg/kg) in saline. These two groups were encoded 0PB and 2PB respectively. Simultaneously, two control groups of rats were injected i.p. with saline only (0 and 2 respectively). PB administration increased relative weight, cytochrome P-450 content and ethoxycoumarin-0-deethylase activity of livers as compared to control rats. In addition, cytochrome P-450-mediated oxidative demethylation of BHA into tert-butyl-hydroquinone (TBHQ), monitored as urinary TBHQ excretion, was significantly increased in PB-induced rats as compared to non-induced rats (0.59 +/- 0.19 versus 0.37 +/- 0.09%; P less than 0.05). The mean labelling index (LI) and potential doubling time (Tpot) in rat forestomach were significantly (P less than 0.01) altered in groups of rats fed 2% BHA as compared to their appropriate control groups. No differences in cell kinetic parameters between either the two control groups (0, 0PB) or between the 2% BHA-fed groups (2, 2PB) was observed. Thus, although an increase in oxidative demethylation of BHA as a response to PB administration is evident, biotransformation of BHA into TBHQ is not correlated to changes in cell kinetic parameters in rat forestomach. Moreover, in rats oxidative cytochrome P-450-mediated demethylation of BHA into TBHQ appears not to be related to the oral dose of BHA. This indicates that oxidative cytochrome P-450-mediated biotransformation of BHA does not contribute to the tumorigenicity of BHA in rat forestomach.
Verhagen
H
H
Department of Human Biology, University of Limburg, Maastricht, The Netherlands.
Furnée
C
C
Schutte
B
B
Hermans
R J
RJ
Bosman
F T
FT
Blijham
G H
GH
ten Hoor
F
F
Henderson
P T
PT
Kleinjans
J C
JC
D000818:Animals; D002083:Butylated Hydroxyanisole / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013270:Stomach / Q000166:cytology* / Q000187:drug effects
D002083:Butylated Hydroxyanisole; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital