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Molecular Pharmacology, Vol 13, 259-268, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics
-Naphthoflavone and 3-Methylcholanthrene as
Inducers of Hepatic Cytochrome(s) P-448 and Aryl Hydrocarbon
(Benzo[a]pyrene) Hydroxylase Activity
1 Developmental Pharmacology Branch, National Institute of Child Health and Human Development, National
Institutes of Health, Bethesda, Maryland 20014
Intraperitoneal 3-methylcholanthrene induces hepatic aryl hydrocarbon (benzo[a]pyrene) hydroxylase (EC 1.14.14.2) in the C57BL/6N mouse about 5-7-fold; a dose of 8O mg/
kg of body weight maintains maximal levels on the second through the seventh day after
a single injection. The same dose of 
-naphthoflavone induces the hydroxylase about 4-fold, the maximal level occurring 40 hr, and the activity returning to basal levels 72 hr,
following a single injection. Dose-response studies, time-response studies, simultaneous
treatment with maximal and submaximal amounts of both inducers, and multiple-injection experiments all suggested that -naphthoflavone is absorbed from the peritoneal cavity much more rapidly than 3-methylcholanthrene. With radiolabeled inducers,
it was confirmed that -naphthoflavone is absorbed from the peritoneal cavity into the
liver and blood and is excreted (presumably as metabolites) in the feces and urine about
10 times more rapidly than 3-methylcholanthrene during the first 12-18 hr after a single
injection of 80 mg/kg of body weight. Concomitant with the rise and fall, respectively, in
-naphthoflavone- or 3-methylcholanthrene-induced aryl hydrocarbon hydroxylase activity are (a) increases and decreases in microsomal total cytochrome P-450 content; (b) a
spectral shift to the blue, and then back toward the red, in the Soret peak of the reduced
cytochrome-CO complex; and (c) and decreases in two bands (having molecular weights
of about 55,500 and 54,500) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Which of the two bands is associated with the induced hydroxylase activity remains
to be determined (or perhaps both bands are). Similar results were found with -naphthoflavone- and 3-methylcholanthrene-treated sexually immature male Sprague-Dawley rats. These data indicate a common mechanism of induction of hepatic cytochrome(s) P-448 by -naphthoflavone and 3-methylcholanthrene.
Note:
ACKNOWLEDGMENTS
We wish to thank Ms. Nancy M. Jensen for her
invaluable technical assistance in this study.
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