Further evidence of cyclic amp-mediated hypertrophy as a prerequisite of drug-specific enzyme induction

Abstract

We have previously reported that the administration of phenobarbital, 3-methylcholanthrene or the polychlorinated biphenyl, Aroclor-1254, to rats resulted in an early and sequential increase in the activities of hepatic cAMP-dependent protein kinase(s), omithine decarboxylase and RNA polymerase I. It was suggested that this sequence of events was involved in both liver hypertrophy and the induction of microsomal mixed-function oxygenases. To further test this hypothesis, we investigated if mice unable to induce aryl hydrocarbon hydroxylase in response to 3-methylcholanthrene exhibited increases in these cAMP-mediated events. A single dose of 3-methylcholanthrene (150 mg/kg, i.p.) was administered to male C57B1/6J (aryl hydrocarbon responsive) and DBA/2J (aryl hydrocarbon nonresponsive) mice. In the C57B1/6J mice, the hepatic cAMP concentration increased to 165 per cent of control within 1 hr. Maximal increases in the activities of liver cAMP-dependent protein kinase(s) (160 per cent), ornithine decarboxylase (210 per cent) and RNA polymerase I (120 per cent) occurred at 2, 4 and 6 hr, respectively, in the responsive mice. There were no detectable increases in any of these parameters in the nonresponsive (DBA/2J) mice. Multiple doses of 3-methylcholanthrene (20 mg/kg, i.p., daily × 3) resulted in increases in hepatic aryl hydrocarbon hydroxylase (460 per cent) and liver weight/body weight ratios (118 per cent) in the responsive (C57B1/6J) mice killed at 5 days. There was no increase in either of these parameters in the nonresponsive (DBA/2J) mice. Both the responsive and nonresponsive mice responded similarly to a single parental dose of phenobarbital (100 mg/kg) with maximal increases in the activities of cAMP-dependent protein kinase(s) (150 per cent), ornithine decarboxylase (160 per cent) and RNA polymerase I (135 per cent) at 2, 4 and 8 hr respectively. Multiple doses of phenobarbital (100 mg/kg, i.p., daily × 3) resulted in increased ethylmorphine N-demethylase activity (160 per cent) and liver weight/body weight ratios (130 per cent) in both strains of mice at 5 days. These data provide further evidence of coupled cAMP-mediated hypertrophy and induction of mixed-function oxygenases in liver.