Mitogenic short-term effects on hepatocytes and adrenocortical cells: phenobarbital and reserpine compared to carcinogenic and non-carcinogenic fluorene derivatives

Summary The adrenal cortex has a low physiologic cell renewal and shows only a moderate cell replication even after contralateral adrenalectomy. Although rather unsusceptible to the malignancy-inducing action of carcinogens, a single oral dose of various tumorigenic xenobiotics induced an additive mitotic response of adrenocortical cells studied after 48 h. Presently we report on three different response patterns in rats. First, a selective mitostimulation of the zona glomerulosa occured after reserpine associated with a loss of body weight, thymus and liver weight. These are unspecific stress effects and occur also after exogenous ACTH. Second, hepatomitogenic and liver-enlarging congeners, e.g. fluorene (FEN), fluorenone (FON) and 4-benzoyl-FON, but also the genotoxic 2-acetyl-aminofluorene (2-AAF) and 2,4,7-trinitro-FON induced a selective mitotic response of the zona fasciculata (ZF). After the lowest effective dose of FEN or FON the afore-mentioned effects occured simultaneously, but were absent in the high dose group (only studied with fluorene). The 2-benzyl and 2-benzoyl-substituted derivatives were ineffective at all. Third, a bizonal response was found only after phenobarbital (PB) or the lowest effective FEN dose. The preventive action of a low PB dose on the 2-AAF-induced ZF response indicates a modified metabolism. We conclude that the rapid mitotic ZF response is an endogeneously mediated net effect of interactions between metabolic and various adaptive mechanisms. The latter are reported to be activated in a stressor-dependent manner and converge in the adrenals. In this way the early mitotic ZF response could reflect indirectly ‘specific’ proliferation-prone properties of xenobiotics.