Cisplatin-Induced Downregulation of OCTN2 Affects Carnitine Wasting.
Summary of "Cisplatin-Induced Downregulation of OCTN2 Affects Carnitine Wasting."
Carnitine is an essential cofactor for mitochondrial fatty acid oxidation that is actively reabsorbed by the luminal transporter Octn2 (Slc22a5). Because the nephrotoxic agent cisplatin causes urinary loss of carnitine in humans, we hypothesized that cisplatin may affect Octn2 function. EXPERIMENTAL
Excretion of carnitine and acetylcarnitine was measured in urine collected from mice with or without cisplatin administration. The transport of carnitine was assessed in cells that were transfected with OCT1 or OCT2. The effect of cisplatin treatment on gene expression was analyzed using a mouse GeneChip array and validated using quantitative reverse transcriptase-PCR.
In wild-type mice, urinary carnitine excretion at baseline was ∼3-fold higher than in mice lacking the basolateral cisplatin transporters Oct1 and Oct2 [Oct1/2(-/-) mice], indicating that carnitine itself undergoes basolateral uptake into the kidney. Transport of carnitine by OCT2, but not OCT1, was confirmed in transfected cells. We also found that cisplatin caused an increase in the urinary excretion of carnitine and acetylcarnitine in wild-type mice but not in Oct1/2(-/-) mice, suggesting that tubular transport of cisplatin is a prerequisite for this phenomenon. Cisplatin did not directly inhibit the transport of carnitine by Octn2 but downregulated multiple target genes of the transcription factor peroxisome proliferator activated receptor α, including Slc22a5, in the kidney of wild-type mice that were absent in Oct1/2(-/-) mice.
Our study shows a pivotal role of Oct1 and Oct2 in cisplatin-related disturbances in carnitine homeostasis. We postulate that this phenomenon is triggered by deactivation of peroxisome proliferator activated receptor α and leads to deregulation of carnitine-shuttle genes. Clin Cancer Res; 16(19); 4789-99. ©2010 AACR.
Authors' Affiliations: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee; Curtin Health Innovation Research Institute, Western Australian Biomedical Research Institute, School of Biomedical Sciences, Curtin U
This article was published in the following journal.
Name: Clinical cancer research : an official journal of the American Association for Cancer Research
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20858838
- DOI: http://dx.doi.org/10.1158/1078-0432.CCR-10-1239
The novel organic cation transporter 2 (OCTN2) is the physiologically most important carnitine transporter in tissues and is responsible for carnitine absorption in the intestine, carnitine reabsorpti...
Cisplatin and its platinum derivatives are first-line chemotherapeutic agents in the treatment of ovarian cancer. However, chemoresistance is the leading cause of therapeutic failure and is responsibl...
Impaired L-carnitine uptake correlates with higher blood pressure in adult men, and L-carnitine restores endothelial function in aortic rings from spontaneously hypertensive rat (SHR). Thus, endotheli...
To evaluate whether PDSC, an l-carnitine ester derivative of prednisolone and OCTN2 substrate, could provide a targeted delivery of the corticosteroid into the lung tissues of an asthmatic guinea pig ...
Chemoresistance is a major challenge in cancer therapy. Cisplatin is commonly used for chemotherapy in patients with head-and-neck cancer (HNC), but it increases control of the disease by only 10-15%....
The current study is part of a large multi-investigator grant to look at the pharmacogenetics of a number of membrane transporters. Previously, the investigators have recruited a cohort o...
Patients with peripheral artery disease have decreased blood flow to exercising muscle causing pain. This decreased blood flow to the muscle affects the level of acylcarnitines which in t...
The purpose of this study is to see if giving nandrolone decanoate (a hormonal drug) will cause weight gain in HIV-positive women who have HIV-associated weight loss (wasting). Wasting ha...
Hemodialysis is a cause of carnitine deficiency. The deficiency of carnitine induces an anemia by an increase fragility of the red blood cells, a muscular fatigue and a cardiac dysfunction...
L-carnitine is a supplement (type of vitamin) that has been suggested to be decreased in patients with cancer. We will identify patients that have terminal cancer and fatigue. The purpos...
Medical and Biotech [MESH] Definitions
An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle.
An enzyme that catalyzes the formation of O-acetylcarnitine from acetyl-CoA plus carnitine. EC 220.127.116.11.
Acyltransferases in the inner mitochondrial membrane that catalyze the reversible transfer of acyl groups from acyl-CoA to L-carnitine and thereby mediate the transport of activated fatty acids through that membrane. EC 2.3.1.
An enzyme that catalyzes the HYDROXYLATION of gamma-butyrobetaine to L-CARNITINE. It is the last enzyme in the biosynthetic pathway of L-CARNITINE and is dependent on alpha-ketoglutarate; IRON; ASCORBIC ACID; and OXYGEN.
A condition of involuntary weight loss of greater then 10% of baseline body weight. It is characterized by atrophy of muscles and depletion of lean body mass. Wasting is a sign of MALNUTRITION as a result of inadequate dietary intake, malabsorption, or hypermetabolism.