Relationship between hepatic peroxisome proliferation and 8-hydroxydeoxyguanosine formation in liver DNA of rats following long-term exposure to three peroxisome proliferators; di(2-ethylhexyl) phthalate, aluminium clofibrate and simfibrate

1区 · 医学

Article

作者: T. Umemura ; K. Sai ; Y. Kurokawa ; R. Hasegawa ; A. Takagi

To elucidate the relationship between hepatic peroxisome proliferation and oxidative DNA damage induced by hepatocarcinogenic peroxisome proliferators, 3 agents, namely, di(2-ethylhexyl) phthalate (DEHP, aluminium clofibrate and simfibrate were fed at doses of 1.2%, aluminium clofibrate 0.5% and 0.5% in the diet, respectively, to male F-344 rats for up to 1 year. Evidence of hepatic peroxisome proliferation and 8-hydroxydeoxyguanosine (8-OH-dG) formation in liver and kidney DNA were assessed at 1, 2, 3, 6, 9 and 12 months. Peroxisomal beta-oxidation enzyme activities were increased 3- to 8-fold and catalase was elevated to 1.4- to 2.2-fold the control level by DEHP, aluminium clofibrate and simfibrate from months 1 to 12 of the treatment. 8-OH-dG levels in liver DNA of DEHP-, aluminium clofibrate- and simfibrate-fed rats were increased approximately 2-fold after 1 month, the tendency for elevation also being observed in the liver DNA at 2, 3, 9 and 12 months. The results thus clearly demonstrate that persistent peroxisome proliferation in the liver leads to continued specific oxidative DNA damage.

1987-11-01·Zhonghua yi xue za zhi = Chinese medical journal; Free China ed

The antilipemic effectiveness of aluminium clofibrate on hyperlipidemic patients with or without diabetes mellitus.

Article

作者: Lam, H C ; Li, S H ; Ho, L T ; Tang, K T ; Wang, J T

1975-04-01·Acta Pharmacologica et Toxicologica

Pharmacokinetics of Clofibrate and Chlorophenoxy Isobutyric Acid. I. Cross‐over Studies on Human Volunteers

Article

作者: Penttila, O. ; Mannisto, P. T. ; Tuomisto, J. ; Jounela, A.

Abstract:The absorption characteristics of five clofibrate preparations were compared in a cross‐over study. After a single dose, four capsule preparations containing 500 mg each of oily clofibrate yielded nearly identical serum levels of chlorophenoxy isobutyric acid (CPIB) in the serum. On the contrary, 500 mg of the basic aluminium salt of CPIB given as a tablet gave significantly lower serum levels at each point of time. The excretion of the latter preparation in 24 hrs was only 1/3 of that of the other four preparations. One of the clofibrate preparations and the tablet preparation were compared in a cross‐over study lasting five days. 500 mg of both drugs were administered twice daily. The capsule preparation gave steady‐state serum levels of 50–65 mg/l of CPIB beginning on the 2nd day. The tablet preparation exhibited a slow rise in the serum levels, and on the 5th day of treatment the differences between the serum levels were no longer significant. The steady‐state and elimination kinetics were studied in a 17‐day hospital experiment. The plateau levels were 65–80 mg/ml after clofibrate 500 mg twice daily, and 50–60 mg/ml after aluminium chlorophenoxy butyrate, respectively. The daily excretion suggested that the absorption of clofibrate is complete, but that that of CPIB is only 60%. Hence, there was a discrepancy between the absorption and the nearly equal steady‐state serum levels. After discontinuing the administration of the aluminium salt, the course of the disappearance of CPIB was first‐order, and an elimination half‐time of 54 hrs was calculated. On the other hand, after clofibrate, a two‐process elimination was seen. The first process had an elimination half‐time of about 10 hrs and the second process had one identical to that observed after Al‐CPIB or 54 hrs. It is suggested that, after clofibrate, CPIB is found in two pools. The rapidly eliminating pool may mainly represent the drug in plasma, whereas the slowly eliminating pool might represent the take up of the drug in the liver and only slowly released into the circulation. When given as CPIB, some of the compound could be trapped by the liver, and then the rate of elimination would depend on the release from the liver. The slow absorption of CPIB and the delayed gastric emptying after Al+++may also contribute to the slow rise in the blood levels. When given as the ester, most of the drug would pass through the liver, and be hydrolyzed in the circulation to give high serum concentrations, and therefore the rate‐limiting step of initial elimination would be the renal handling of the drug. Some redistribution is also likely to take place at this initial stage.

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