Relationship between hepatotoxicity and induction of replicative DNA synthesis following single or multiple doses of carbon tetrachloride

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Abstract
The in vivo‐in vitro DNA repair and DNA replication assay in mouse hepatocytes has promise as a short‐term test for detecting potential mouse liver carcinogens. In addition, this assay may provide information on the mode of action of known hepatic carcinogens. The induction of DNA repair is clearly a response to hepatic DNA damage. However, it is unclear whether induction of replicative DNA synthesis (S phase) represents regenerative hyperplasia in response to hepatotoxicity or is a result of direct mitogenic stimulation of the hepatocytes by the test compound. The objective of the present study was to examine the relationship between hepatotoxicity, which was assessed by measuring serum concentrations of glutamic‐oxalacetic transaminase (SCOT), glutamic‐pyruvic transaminase (SCPT), alkaline phosphatase (AP), and gammaglutamyl transferase (CGT), and induction of S phase following either single or multiple doses of the model mouse hepatocarcinogen carbon tetrachloride (CCI 4 ). Under the experimental conditions in this study, CCI 4 elevated SCPT and SCOT but did not affect serum concentrations of AP or CCT. CCI 4 did not induce DNA repair. An increase in the percentage of hepatocytes in S phase followed the appearance of elevated SCOT and SCPT in all single‐dose studies. The results from the multipledose studies showed a similar relationship except that with 20 mg/kg • d the concentrations of SGOT and SCPT decayed to control values after 14 d of dosing whereas the percentage of hepatocytes in S phase remained markedly elevated (>10× control). The daily dose of CCI 4 that gave a no‐observed‐effect level for induction of S phase was lower with multiple administrations than it was following a single exposure. A single administration of CCI 4 at 25 mglkg did not increase S phase, SCOT, or SCPT, but if 20 mglkg • d was given for 7 d the number of hepatocytes in S phase and the concentrations of SCOT and SGPT increased more than 10‐fold. These data support the hypothesis that induction of replicative DNA synthesis in the mouse liver following CC/ 4 administration is related to hepatotoxicity. In single‐dose studies elevation in S phase was always associated with elevation of SCOT and SCPT. However, in the multidose studies, SGOT and SGPT declined after 14 d of administering 20 mglkg • d while S phase remained elevated. This indicates that S‐phase analysis may be a more sensitive and/or persistent index of adverse biological effects in the liver than serum enzyme analysis when multidose protocols are used.