Cyclophosphamide induces mRNA, protein and enzyme activity of cytochrome P450 in rat

Xie, Hua; Afsharian, Parvaneh; Terelius, Ylva; Ra, Mirghani; Yaşar, Ümit; Al, Hagbjörk; Lundgren, Stefan; Hu, Yuanliang; Rane, Anders; Hassan, Manal M.

doi:10.1080/00498250500057369

Cited by 15 publications

(15 citation statements)

References 24 publications

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“…It appeared reasonable that there was some commonality between CPA and APAP, because these drugs damage cells in a similar manner; reactive metabolites of these drugs covalently bind to DNA or proteins. Decreased Cyp3a3 (Table 3C) was consistent with a previous in vivo study in rats, whereas no increases of Cyp2b or Cyp2c, which have been reported in the in vivo study (Xie et al, 2005), were observed. Increased Hmox1 may be consistent with a previous report that showed increased heme oxygenase content in the liver in rats in vivo (Rizzardini et al, 1984).…”

Section: Drugs Not Directly Toxic To Hepatocytes In Vivo or Rarely Tosupporting

confidence: 81%

In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes

Suzuki¹,

Inoue²,

Matsushita³

et al. 2008

J of Applied Toxicology

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The study examined the feasibility of screening for hepatotoxicity by an in vitro gene expression analysis using rat primary hepatocytes and Affymetrix Rat Toxicology U34 arrays. Hepatocytes were exposed for 6 or 24 h to eight drugs, with different mechanisms of hepatotoxicity, at one third of the cytotoxic concentration TC 50 , i.e. acetaminophen, cyclophosphamide, clofibrate, chlorpromazine, lithocholic acid, cisplatin, diclofenac and disulfiram. The types of transcriptional changes observed in this study were generally consistent with previously reported in vivo data, although there were some differences. In hierarchical cluster analysis, drugs formed clusters depending on their mode of toxicity against cells. The number of transcripts affected by the cholestatic hepatotoxicants (lithocholic acid and chlorpromazine) or the drugs that rarely cause of hepatotoxicity (cisplatin, diclofenac and disulfiram) were limited compared with the other drugs (acetaminophen, clobifibrate and cyclophosphamide), where they did not induce transcriptional changes apparently related to toxicity. It is concluded that in vitro gene expression analysis of hepatocytes using microarray is a useful tool for evaluating the toxicological profile of drugs and in screening for the direct toxicity of drugs against hepatocytes.

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Section: Drugs Not Directly Toxic To Hepatocytes In Vivo or Rarely Tosupporting

confidence: 81%

In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes

Suzuki¹,

Inoue²,

Matsushita³

et al. 2008

J of Applied Toxicology

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“…CP itself is devoid of alkylating activity and must first undergo bioactivation by hepatic microsomal cytochrome P450 mixed function oxidase system (COLVIN, 1999;PASS et al, 2005;XIE et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Exercise protects rat testis from cyclophosphamide-induced damage

Ramos

Goessler

Ruíz

et al. 2013

Acta Sci. Biol. Sci.

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ABSTRACT.To investigate the effect of chronic moderate exercise on male reproductive tract of Wistar rats submitted to a single dose of cyclophosphamide (CP). Animals were submitted to swimming exercise during 21 days or maintained at sedentary state. Trained (TCP) and sedentary (SCP) groups received a single dose of CP (200 mg kg -1 , i.p.). Trained (TCo) and sedentary (SCo) control animals received sterile PBS. Animals were killed after one week and testis, epidydimis and seminal vesicle contend were weighted. Testis were embebbed in parafim and stained with hemotaxilin and eosin. Fifty seminiferous tubules of each animal were analyzed by Johnsen score. Mean Sertoli cells counts per tubule and Leydig cells counts per area were evaluated. CP treatment impairs body weight gain in trained and sedentary animals. Liver and seminal vesicle contend were reduced only in SCo group. SCP animals presented decreased Johnsen scores, indicating a slight toxicity over germinative cells, whereas trained (TCo and TCP) animals presented increased Johnsen scores. Training increased Sertoli cell counts and prevented their loss in TCP group. Leydig cells counts were increased in trained animals, but decreased in CP treated ones (TCP). We conclude that exercise have some protective effect on male reproductive tract submitted to a single dose of CP. , ip). Os animais treinados (TCO) e sedentários (SCO) receberam PBS estéril. Os animais foram sacrificados após uma semana e os testículos, epidídimo e conteúdo da vesícula seminal foram pesados. As amostras foram embebidas em parafina e coradas com hematoxilina e eosina. Cinquenta túbulos seminíferos de cada animal foram analisados pelo escore Johnsen. A contagem média das células de Sertoli por túbulo e contagem das células de Leydig por área foram avaliadas. O tratamento CP prejudicou o ganho de peso corporal em animais treinados e sedentários. O fígado e o conteúdo da vesícula seminal foram reduzidos apenas no grupo SCO. Os animais SCP apresentaram menores escores de Johnsen, indicando uma toxicidade moderada sobre as células germinativas, enquanto os animais treinados (TCO e TCP) apresentaram escores de Johnsen mais altos. O treinamento aumentou a contagem de células de Sertoli e impediu a sua perda no grupo TCP. A contagem das células de Leydig foram aumentadas em animais treinados, mas reduzidas nos animais tratados com CP (TCP). Concluiu-se que o exercício tem algum efeito protetor sobre trato reprodutivo masculino de animais submetidos a uma dose única de CP.Palavras-chave: ciclofosfamida, exercício, trato reprodutiva.

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“…The maximum levels of mRNA were reached between 4 and 8 h after the administration of a single dose. A decrease in CPA concentration and an increase in 4-OH-CPA levels after repeated administration were observed (25).…”

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confidence: 99%

“…The remaining plasma was stored at -70jC until assayed for CPA. Livers were removed, snapped frozen in liquid nitrogen, and kept at -70jC for subsequent total RNA extraction and microsomal preparation (25,27).…”

Section: Chemicalsmentioning

confidence: 99%

“…However, these studies were carried out 6 to 14 days after CPA treatment (4, 20 -24). Recently, we (25) have shown that induction effect of CPA on CYPs in rats occurred within 5 days after a single administration of CPA. The induction of mRNA, protein, and microsomal activity of CYP2B1, CYP2B2, CYP3A2, and CYP2C11 was observed after both high and low doses of CPA in rats.…”

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confidence: 99%

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The Effect of Repeated Administration of Cyclophosphamide on Cytochrome P450 2B in Rats

Afsharian¹,

Terelius²,

Hassan³

et al. 2007

Clinical Cancer Research

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Purpose: The prodrug cyclophosphamide (CPA) is activated by cytochrome P450 (CYP) enzymes. CPA is one of the corner stones in all cancer treatment. We have studied the effect of repeated doses of CPA given at different time intervals on the mRNA, protein levels, and enzyme activity of CYPs in rats. Experimental Design: Two groups of animals (A-75 and A-150) were treated with four doses of CPA (75 and 150 mg/kg, respectively) at short time intervals (6 h). The third group of animals (B-150) was treated with 150 mg/kg at 24-h intervals. Three animals were killed 30 min after administration, and three animals immediately before the next dose. Results: CYP2B1 and CYP2B2 mRNAs were significantly induced at 6 h after each dose in group A-75 (maximum of 2100-fold and 60-fold after the third dose, respectively), whereas the mRNA levels measured at 6 h postadministration in group A-150 were 1,490-fold and 36-fold after the second dose. In group B-150, no significant induction of mRNA levels was observed. CYP2B1 and CYP2B2 protein levels also increased with increased mRNAs. Plasma levels of 4-hydroxy-CPA measured at 30 min after dose correlated well with the increase in protein levels. Conclusion: Up-regulation of CYP2B mRNA, with a concomitant increase in protein expression and activity, were observed after repeated administration of low doses of CPA compared with that found using higher doses, possibly due to toxicity counteracting induction. These results may help in designing more effective dosing schedules for CPA.

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Cyclophosphamide induces mRNA, protein and enzyme activity of cytochrome P450 in rat

Cited by 15 publications

References 24 publications

In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes

In vitro gene expression analysis of hepatotoxic drugs in rat primary hepatocytes

Exercise protects rat testis from cyclophosphamide-induced damage

The Effect of Repeated Administration of Cyclophosphamide on Cytochrome P450 2B in Rats

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