Induction of benzpyrene hydroxylase by flavone and its derivatives in fetal rat liver explants

doi:10.1016/0006-2952(72)90398-X

Biochemical Pharmacology

Volume 21, Issue 7, 1 April 1972, Pages 937-945

https://doi.org/10.1016/0006-2952(72)90398-X Get rights and content

Abstract

Fetal rat liver organ culture affords a system for the comparison of the mechanism(s) of induction^∗ of benzpyrene (BP) hydroxylase by flavones and 3-methyl-cholanthrene(3-MC). Flavone and β-naphthoflavone (BNF) were equally potent inducers at 10⁻⁵ M. 4′-halogenated flavone derivatives proved even more effective in this regard; flavanone and the naturally occuring flavone, tangeretin, were inactive. Although BP hydroxylase activity was inhibited by BNF, 3-MC or 4′-bromoflavone when added to homogenates of fetal rat liver explants, no interference by the inducer was observed under the experimental conditions employed in this study. When equal amounts of the induced and control enzyme were mixed, no less than additive enzyme activity was observed. Flavone derivatives and 3-MC appear to act by a similar mechanism in elevating BP hydroxylase, since combinations of inducers at unsaturating levels resulted in an additive effect, while at saturating levels, enzyme induction was no greater than that of the most potent agent alone.

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The inducing effects of some flavonoids (flavone, flavanone, tangeretin and quercetin) and model substances have been studied in rats, and the activity and the expression of drug-metabolizing enzymes have been compared in rats. The addition of flavonoids to the diet (0.3% w/w) for 2 weeks did not change the liver cytochrome P450 content nor the activities of the NADPH-cytochrome P450 and NADH-cytochrome b₅ reductases, but it affected the activities of phase I and phase II enzymes. Flavone, and to a lesser extent tangeretin, increased the activities mediated by the P450 1A1,2 (EROD) and 2B1,2 (PROD) as well as the activities of p-nitrophenol UDP-glucuronyl transferase (UGT) and glutathione transferase (GST). Flavanone mainly enhanced PROD, UGT and GST, whereas quercetin did not modify any enzyme activities. None of the tested flavonoids modulated the activities catalyzed by P450 2E1, 3A and 4A. Immunoblotting studies showed that flavone and tangeretin increased the expression of cytochrome P450 1A and 2B forms, whereas flavanone only induced cytochrome P450 2B. Flavone and to a lesser extent flavanone, markedly increased the phenol-UGT protein level. Both flavone and flavanone also increased the androsterone- and testosterone-UGTs, whereas tangeretin and quercetin did not increase any UGT isoform. We concluded that the flavonoids tested specifically affected the expression of the drug-metabolizing isozymes in rat liver, their inducing properties were dependent on their chemical structures.
Modulating effects of β-naphthoflavone on the induction of SCEs by model compounds with emphasis on benzo[a]pyrene
1988, Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
The inducing capability of the synthetic flavonol β-naphthoflavone (β-NF) on cytochrome P-450 content was studied in primary chick embryo hepatocytes. In addition, the modulating effects of pretreatment with β-NF on the induction of siste-chromatid exchanges (SCEs) in V79 cells by mutagens from different chemical classes were investigated in a co-cultivation system consisting of primary chick embryo hepatocytes and V79 Chinese hamster cells. Finally, the effects of pretreatment on benzo[a]pyrene (B(a)P) metabolism were studied in more detail. Pretreatment of cultured primary chick embryo hepatocytes with β-NF resulted in a large increase in cytochrome P-450 content (a 2.8-fold increase after 31 h). Pretreatment with β-NF had no effect on the level of SCEs induced by N-nitroso-dimethylamine (NDMA) and 2-aminoanthracene (2AA). Pretreatment with β-NF resulted in a decrease in B(a)P-induced SCEs. This inhibitory potential was positively related to the β-NF dose. However, there was an inverse relationship between the inhibitory action of β-NF and the dose of B(a)P, at higher doses less inhibition was observed. When β-NF was applied simultaneously with B(a)P the percentage of decrease was about the same as for pretreatment. Pretreatment with β-NF followed by simultaneous application of β-NF and B(a)P did not result in larger effects.
Comparison of the effects of feeding quercetin or flavone on hepatic and intestinal drug-metabolizing enzymes of the rat
1988, Food and Chemical Toxicology
The influence of dietary flavone and quercetin on the components of the drug metabolizing enzyme system was examined in the liver and small intestine of the rat. Quercetin given at a concentration of 1% in the diet for 14 days produced no significant changes on phase I or phase II enzyme activities. In contrast, 0.25% flavone caused significant increases in relative liver weight, microsomal and cytoplasmic proteins, and cytochrome P-450 content. The activities of hepatic ethoxyresorufin, pentoxyresorufin and ethoxycoumarin deethylases were significantly increased (by 20, 30 and 2.5-fold, respectively) over control levels. Hepatic UDP-glucuronyl transferase and glutathione transferase activities were increased 3–4-fold. In contrast, flavone induced no changes in these two intestinal enzyme activities. It is concluded that flavone produces an induction that shows both phenobarbital- and methylcholanthrene-type characteristics and that its effect on conjugating enzymes is tissue specific.
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The risks to humans of serious poisonous effects caused by natural phenols present in normal foods consumed under usual circumstances seem vanishingly small, as determined by experiment, as well as common sense and long-term observation. Conclusions involving evolution obviously are speculative, but some putative relationships appear worthy of discussion to clarify the durability of animal life and the threat of plant toxins generally or of phenols particularly. Phenols are probably the most important group of substances, useful in chemotaxonomic differentiation among plant species. Plants have evolved toxins to combat herbivores, but herbivores have also evolved to tolerate or avoid plant toxins. Phenol itself, and other small phenols, such as catechol, the cresols, guaiacol, orcinols, and pyrogallol, are commonly considered to be industrial chemicals. Gallic acid is widely distributed in plants, but the concentration is usually very low. The flavonoids contribute color, flavor, and processing characteristics important in food. The most often cited effect of phenols that is discussed in this chapter is the inhibition of catechol-O-methyltransferse (COMT) and competition for methyl groups by phenols that serve as a substrate for this enzyme. The chapter discusses that many plants contain secondary metabolites toxic or deterrent to members of the animal kingdom attempting to feed on them. Plant phenols that are highly toxic to animals are rarely found. The phenols that occur widely in plants or in large amounts in common food plants have very low acute oral toxicity and most are also of low toxicity when given parenterally.
[5] The Fetal Rat Liver Explant as a Model System in the Study of Hormone Action
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Induction of benzpyrene hydroxylase by flavone and its derivatives in fetal rat liver explants

Abstract

Adv. Pharmac.

J. biol. Chem.

Archs Biochem. Biophys.

J. biol. Chem.

J. biol. Chem.

J. biol. Chem.

J. Pharmac. exp. Ther.

Pharmac. Rev.

Clin. Pharmac. Ther.

Cancer Res.