Al Kholaifi, Abdullah
(2008)
The induction of liver growth by peroxisome proliferators.
PhD thesis, University of Nottingham.
Abstract
Peroxisome Proliferators (PPs) are a class of chemicals that cause a programme of augmentative liver growth, however, the mechanism which regulates the induction of hepatic DNA synthesis as a result of exposure to peroxisome proliferators is currently uncharacterized.
This study sets out to characterise the induction of DNA synthesis in mouse by peroxisome proliferators, as a prerequisite for investigating and identifying the genes that are responsible for induction of DNA synthesis to control liver growth.
Administration of BrdU in drinking water can reduce mouse body weight; an optimized protocol was devised, which does not lead to body weight loss, and which enables reliable measurement of DNA synthesis.
Male 129S4/SvJae mice were treated with a single dose of ciprofibrate (100-400 mg kg-1) or methylclofenapate (25 mg kg-1) for two days.
Although liver to body weight ratios increased significantly at all doses, no induction in DNA synthesis was observed within 2 days. Subsequent time course studies with ciprofibrate (100 mg kg-1day-1) or methylclofenapate (25 mg kg-1day-1) showed that liver-to-body weight ratio was significantly increased in treated groups by day 2, but that the induction of DNA synthesis was increased significantly only after three days of treatment, for both compounds. No induction of hepatic DNA synthesis was observed in PPARa null mice after treatment with ciprofibrate (100mg kg-1day-1) for 2 or 6 days, showing that the effect required the PPARa.
A dose-response study with 0,1,3,10,30,100 or 200 mg kg-1 day-1 ciprofibrate for 3 days, or with 0,10,30,100 mg kg-1 day-1 ciprofibrate for 4 days revealed that liver to body weight ratios were significantly increased in 129S4/SvJae mice treated with 10mg kg-1day-1 and greater ciprofibrate at 3 and 4 days, whereas hepatic labelling index was significantly increased at 100 mg kg-1 day-1 ciprofibrate at 3 days after dosing, with progressive increases at doses of 30 and 100 mg kg-1 day-1 ciprofibrate at 4 days after dosing.
In order to explain the early time course of induction of DNA synthesis reported by Styles [113] [164] in Alderley Park mice, a time course study was performed between 1-4 days in Alderley park mice using methylclofenapate (25mg kg-1day-1). The study showed that liver growth was induced by day 2, but DNA synthesis was significantly induced only after 3 days of dosing.
To evaluate species differences, the time-course of induction of DNA synthesis was examined in F-344 rats treated with ciprofibrate (50mg kg-1day-1) for 1-4 days. The liver-to-body weight ratio was significantly increased in all time points, but DNA synthesis was significantly increased after 2 days of dosing.
These findings demonstrate that there was a delay in induction of DNA synthesis by peroxisome proliferators in mouse by at least 48 hours. This delay in response is not due to strain differences. Moreover, induction of DNA synthesis in rat was earlier than those in mouse, which makes rats a feasible experimental model to study the immediate early genes/ proteins induced by peroxisome proliferators to induce liver growth.
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