Nucleic Acid and Pyrimidine Nucleotide Metabolism During Liver Growth Induced by Xenobiotic Compounds

Abstract

Administration of lipid-soluble drugs — α-hexachlorocyclohexane (α-HCH), phenobarbital (PB) and butylated hydroxytoluene (BHT) induce the mixed-function oxidase (MFO) of hepatic microsomes. Simultaneously the growth of the liver is evoked; hypertrophy and hyperplasia are involved to different extents (R. Schulte-Hermann, Crit. Rev. Toxicol., 3, 97, 1974). The administration of inducers is accompanied by the activation of the synthesis and the inhibition of the degradation of different cellular components of the liver including RNA. Following the administration of α-HCH, PB and BHT the utilization of labeled orotic acid for the synthesis of uridine components of the acid-soluble nucleotides and RNA uracil is increased while for the synthesis of cytidine components it is decreased. Simultaneously the transport of exogenously injected labeled cytidine into liver is activated. The uptake of labeled cytidine by the liver proceeds as a nonsaturable transport process over a wide dose range of nucleoside injected (0.003–100 μmol per rat). In α-HCH treated animals the transport of labeled cytidine is markedly activated if the dose of injected nucleoside is low; the differences between the control and experimental groups disappear at high doses of cytidine. The specific activity of RNA cytosine decreases in proportion to the logarithm of cytidine dose, both in control and experimental groups. Analogically the incorporation of labeled cytidine into RNA cytosine is enhanced in α-HCH treated rats at the low doses of cytidine injected; the differences are abolished following the application of high doses of nucleoside. The decreased utilization of labeled orotic acid for synthesis of cytidine nucleotides is not caused by the inhibition of cytidine triphosphate synthetase of liver cytosol. Following the administration of α-HCH and PB the activity of this enzyme estimated in vitro is enhanced. The concentration of cytidine and uridine components of acid-soluble extract, however, is not significantly affected. The decreased utilization of labeled orotic acid for the synthesis of cytidine components and increased transport of labeled cytidine into the liver after the administration of the drugs is apparently unrelated to the increased mitotic activity of the liver; both phenomena as well as the increased level of microsomal cytochrome P-450 and demethylating activity occur after the administration of low doses of α-HCH (5 mg/kg) where no increase of liver mass and no activation of DNA synthesis could be registered (R. Schulte-Hermann, C. Leberl, H. Landgraf and W. Koransky, Naunyn-Schmiedeberg’s Arch. Pharmacol. 285, 355, 1974). In addition in regenerating rat liver the utilization of labeled orotic acid for the synthesis of cytidine nucleotides is markedly enhanced, without any detectable changes in the uptake of labeled cytidine, its phosphorylation and utilization for RNA synthesis (N. L. R. Bucher and M. N. Swaffield, Biochim. Biophys. Acta 174, 491, 1969; M. G. Ord and J. E. Stocken, Biochem. J. 132, 47, 1973; E. L. Krawitt, I. Betel and V. R. Potter, Biochim. Biophys. Acta 174, 763, 1969). These differences show: (a) that the changes in the metabolism, transport and utilization of cytidine are connected rather with the development of MFO induction than with enhanced proliferation in the liver; (b) that the induction of MFO and growth promoting effect may be distinguished by the use of certain inducer at a certain dose level. The increased reutilization of preformed cytidine after the administration of inducing drugs may be caused by an increased need for the synthesis of cytidine cofactors of phospholipids synthesis or increased RNA synthesis in liver cells which is not paralleled in proportion of its enhanced de novo synthesis.