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Inhibition of gene expression of organic cation/carnitine transporter and antioxidant enzymes in oxazaphosphorines-induced acute cardiomyopathic rat models.

Sayed-Ahmed MM, Aldelemy ML, Hafez MM, Al-Shabanah OA - Oxid Med Cell Longev (2012)

Bottom Line: It is well documented that high therapeutic doses of oxazaphosphorines, cyclophosphamide (CP) and ifosfamide (IFO), are associated with cardiomyopathy.In cardiac and kidney tissues, CP and IFO significantly decreased mRNA and protein expression of OCTN2.Data from this study suggest that: (1) Oxazaphosphorines decreased myocardial carnitine content following the inhibition of OCTN2 mRNA and protein expression in cardiac tissues. (2) Oxazaphosphorine therapy increased urinary loss of carnitine secondary to the inhibition of OCTN2 mRNA and protein expression in proximal tubules of the kidney. (3) Carnitine supplementation attenuates CP but not IFO-induced inhibition of OCTN2 mRNA and protein expression in heart and kidney tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. sayedahmedmm@hotmail.com

ABSTRACT
It is well documented that high therapeutic doses of oxazaphosphorines, cyclophosphamide (CP) and ifosfamide (IFO), are associated with cardiomyopathy. This study investigated whether oxazaphosphorines alter the expression of organic cation/carnitine transporter (OCTN2) and antioxidant genes and if so, whether these alterations contribute to CP and IFO-induced cardiotoxicity. Adult male Wistar albino rats were assigned to one of six treatment groups namely, control, L carnitine, CP, IFO, CP plus L carnitine and IFO plus L carnitine. In cardiac and kidney tissues, CP and IFO significantly decreased mRNA and protein expression of OCTN2. Oxazaphosphorines significantly increased serum acyl-carnitine/free carnitine ratio and urinary carnitine excretion and significantly decreased total carnitine in cardiac tissues. Interestingly, carnitine supplementation completely reversed the biochemical and gene expression changes-induced by oxazaphosphorines to the control values, except OCTN2 expression remained inhibited by IFO. Data from this study suggest that: (1) Oxazaphosphorines decreased myocardial carnitine content following the inhibition of OCTN2 mRNA and protein expression in cardiac tissues. (2) Oxazaphosphorine therapy increased urinary loss of carnitine secondary to the inhibition of OCTN2 mRNA and protein expression in proximal tubules of the kidney. (3) Carnitine supplementation attenuates CP but not IFO-induced inhibition of OCTN2 mRNA and protein expression in heart and kidney tissues.

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Related in: MedlinePlus

Effects of cyclophosphamide (CP), ifosfamide (IFO), L carnitine (LC), and their combination on the levels of total carnitine in rat heart tissues. Rats were randomly divided into 6 different groups of 10 animals each: control, L carnitine, CP, IFO, CP carnitine supplemented and IFO carnitine-supplemented. Carnitine supplementation was induced in rats by daily intraperitoneal injection of L carnitine (200 mg/kg/day) for 10 successive days. CP cardiotoxicity was induced in rats by administration of a single dose of CP (200 mg/kg). IFO cardiotoxicity was induced in rats by administration of IFO (50 mg/kg/day, I.P.) for 5 successive days. CP-carnitine supplemented rats were given the same doses of L carnitine (200 mg/kg/day) for 5 days before and 5 days after a single dose of CP (200 mg/kg). IFO-carnitine supplemented rats were given the same doses of L carnitine (200 mg/kg/day) for 5 days before and 5 days concomitant with IFO (50 mg/kg/day, I.P.). At the end of the treatment protocol, total carnitine was measured in heart tissues. Data are presented as mean ± S.E.M. (n = 10). *, #, and $ indicate significant change from control, CP and IFO, respectively, at P < 0.05 using ANOVA followed by Tukey-Kramer as a post-ANOVA test.
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fig3: Effects of cyclophosphamide (CP), ifosfamide (IFO), L carnitine (LC), and their combination on the levels of total carnitine in rat heart tissues. Rats were randomly divided into 6 different groups of 10 animals each: control, L carnitine, CP, IFO, CP carnitine supplemented and IFO carnitine-supplemented. Carnitine supplementation was induced in rats by daily intraperitoneal injection of L carnitine (200 mg/kg/day) for 10 successive days. CP cardiotoxicity was induced in rats by administration of a single dose of CP (200 mg/kg). IFO cardiotoxicity was induced in rats by administration of IFO (50 mg/kg/day, I.P.) for 5 successive days. CP-carnitine supplemented rats were given the same doses of L carnitine (200 mg/kg/day) for 5 days before and 5 days after a single dose of CP (200 mg/kg). IFO-carnitine supplemented rats were given the same doses of L carnitine (200 mg/kg/day) for 5 days before and 5 days concomitant with IFO (50 mg/kg/day, I.P.). At the end of the treatment protocol, total carnitine was measured in heart tissues. Data are presented as mean ± S.E.M. (n = 10). *, #, and $ indicate significant change from control, CP and IFO, respectively, at P < 0.05 using ANOVA followed by Tukey-Kramer as a post-ANOVA test.

Mentions: Figure 3 shows the effects of oxazaphosphorines, L carnitine, and their combination on total carnitine levels in rat cardiac tissues. Administration of a single dose of CP and 5 doses of IFO resulted in a significant 52 and 41% decrease in total carnitine level in heart tissues, respectively, as compared to the control group. On the other hand, daily administration of L carnitine alone for 10 successive days resulted in a significant 47% increase as compared to the control rats. Interestingly, administration of L carnitine in combination with CP and IFO resulted in a complete reversal of the decrease in myocardial carnitine content, induced by CP and IFO, to the control values.


Inhibition of gene expression of organic cation/carnitine transporter and antioxidant enzymes in oxazaphosphorines-induced acute cardiomyopathic rat models.

Sayed-Ahmed MM, Aldelemy ML, Hafez MM, Al-Shabanah OA - Oxid Med Cell Longev (2012)

Effects of cyclophosphamide (CP), ifosfamide (IFO), L carnitine (LC), and their combination on the levels of total carnitine in rat heart tissues. Rats were randomly divided into 6 different groups of 10 animals each: control, L carnitine, CP, IFO, CP carnitine supplemented and IFO carnitine-supplemented. Carnitine supplementation was induced in rats by daily intraperitoneal injection of L carnitine (200 mg/kg/day) for 10 successive days. CP cardiotoxicity was induced in rats by administration of a single dose of CP (200 mg/kg). IFO cardiotoxicity was induced in rats by administration of IFO (50 mg/kg/day, I.P.) for 5 successive days. CP-carnitine supplemented rats were given the same doses of L carnitine (200 mg/kg/day) for 5 days before and 5 days after a single dose of CP (200 mg/kg). IFO-carnitine supplemented rats were given the same doses of L carnitine (200 mg/kg/day) for 5 days before and 5 days concomitant with IFO (50 mg/kg/day, I.P.). At the end of the treatment protocol, total carnitine was measured in heart tissues. Data are presented as mean ± S.E.M. (n = 10). *, #, and $ indicate significant change from control, CP and IFO, respectively, at P < 0.05 using ANOVA followed by Tukey-Kramer as a post-ANOVA test.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369488&req=5

fig3: Effects of cyclophosphamide (CP), ifosfamide (IFO), L carnitine (LC), and their combination on the levels of total carnitine in rat heart tissues. Rats were randomly divided into 6 different groups of 10 animals each: control, L carnitine, CP, IFO, CP carnitine supplemented and IFO carnitine-supplemented. Carnitine supplementation was induced in rats by daily intraperitoneal injection of L carnitine (200 mg/kg/day) for 10 successive days. CP cardiotoxicity was induced in rats by administration of a single dose of CP (200 mg/kg). IFO cardiotoxicity was induced in rats by administration of IFO (50 mg/kg/day, I.P.) for 5 successive days. CP-carnitine supplemented rats were given the same doses of L carnitine (200 mg/kg/day) for 5 days before and 5 days after a single dose of CP (200 mg/kg). IFO-carnitine supplemented rats were given the same doses of L carnitine (200 mg/kg/day) for 5 days before and 5 days concomitant with IFO (50 mg/kg/day, I.P.). At the end of the treatment protocol, total carnitine was measured in heart tissues. Data are presented as mean ± S.E.M. (n = 10). *, #, and $ indicate significant change from control, CP and IFO, respectively, at P < 0.05 using ANOVA followed by Tukey-Kramer as a post-ANOVA test.
Mentions: Figure 3 shows the effects of oxazaphosphorines, L carnitine, and their combination on total carnitine levels in rat cardiac tissues. Administration of a single dose of CP and 5 doses of IFO resulted in a significant 52 and 41% decrease in total carnitine level in heart tissues, respectively, as compared to the control group. On the other hand, daily administration of L carnitine alone for 10 successive days resulted in a significant 47% increase as compared to the control rats. Interestingly, administration of L carnitine in combination with CP and IFO resulted in a complete reversal of the decrease in myocardial carnitine content, induced by CP and IFO, to the control values.

Bottom Line: It is well documented that high therapeutic doses of oxazaphosphorines, cyclophosphamide (CP) and ifosfamide (IFO), are associated with cardiomyopathy.In cardiac and kidney tissues, CP and IFO significantly decreased mRNA and protein expression of OCTN2.Data from this study suggest that: (1) Oxazaphosphorines decreased myocardial carnitine content following the inhibition of OCTN2 mRNA and protein expression in cardiac tissues. (2) Oxazaphosphorine therapy increased urinary loss of carnitine secondary to the inhibition of OCTN2 mRNA and protein expression in proximal tubules of the kidney. (3) Carnitine supplementation attenuates CP but not IFO-induced inhibition of OCTN2 mRNA and protein expression in heart and kidney tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. sayedahmedmm@hotmail.com

ABSTRACT
It is well documented that high therapeutic doses of oxazaphosphorines, cyclophosphamide (CP) and ifosfamide (IFO), are associated with cardiomyopathy. This study investigated whether oxazaphosphorines alter the expression of organic cation/carnitine transporter (OCTN2) and antioxidant genes and if so, whether these alterations contribute to CP and IFO-induced cardiotoxicity. Adult male Wistar albino rats were assigned to one of six treatment groups namely, control, L carnitine, CP, IFO, CP plus L carnitine and IFO plus L carnitine. In cardiac and kidney tissues, CP and IFO significantly decreased mRNA and protein expression of OCTN2. Oxazaphosphorines significantly increased serum acyl-carnitine/free carnitine ratio and urinary carnitine excretion and significantly decreased total carnitine in cardiac tissues. Interestingly, carnitine supplementation completely reversed the biochemical and gene expression changes-induced by oxazaphosphorines to the control values, except OCTN2 expression remained inhibited by IFO. Data from this study suggest that: (1) Oxazaphosphorines decreased myocardial carnitine content following the inhibition of OCTN2 mRNA and protein expression in cardiac tissues. (2) Oxazaphosphorine therapy increased urinary loss of carnitine secondary to the inhibition of OCTN2 mRNA and protein expression in proximal tubules of the kidney. (3) Carnitine supplementation attenuates CP but not IFO-induced inhibition of OCTN2 mRNA and protein expression in heart and kidney tissues.

Show MeSH
Related in: MedlinePlus