RESUMO
Carnitine octanoyltransferase (COT), which facilitates the transport of shortened fatty acyl-CoAs from peroxisomes to mitochondria, is expressed in the intestinal mucosa of suckling rats; its mRNA levels increase rapidly after birth, remain steady until day 15, and decrease until weaning, when basal, adult values are established, which remain unchanged thereafter. The process seems to be controlled at the transcriptional level since the developmental pattern of mRNA coincides with that of pre-mRNA values. Dam's milk may influence the intestinal expression of COT, since mRNA levels at birth are low and increase after the first lactation. Moreover, mRNA levels decrease in rats weaned on day 18 or 21. COT is also expressed in the liver of suckling rats. Hepatic COT mRNA is maximal at day 3, remains constant until day 9, and decreases thereafter; this pattern is also similar to that of pre-mRNA values. The profile of expression of COT in intestine and liver strongly resembles that of mitochondrial 3-hydroxy 3-methylglutaryl-coenzyme A synthase and carnitine palmitoyltransferase I, suggesting that analogous transcription factors modulate ketogenesis and mitochondrial and peroxisomal fatty acid oxidation.
Assuntos
Carnitina Aciltransferases/genética , Regulação Enzimológica da Expressão Gênica , Intestinos/enzimologia , Fígado/enzimologia , Animais , Animais Recém-Nascidos , Animais Lactentes , Sequência de Bases , Carnitina Aciltransferases/metabolismo , Éxons/genética , Perfilação da Expressão Gênica , Mucosa Intestinal/citologia , Mucosa Intestinal/enzimologia , Mucosa Intestinal/metabolismo , Intestinos/citologia , Íntrons/genética , Fígado/citologia , Fígado/metabolismo , Dados de Sequência Molecular , Músculo Liso/enzimologia , Músculo Liso/metabolismo , Peroxissomos/enzimologia , Peroxissomos/metabolismo , Precursores de RNA/genética , Precursores de RNA/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Transcrição Gênica/genética , DesmameRESUMO
BACKGROUND: Fluoropyrimidines may be effective in preventing proliferative vitreoretinopathy after repair of complicated retinal detachments. Liposome encapsulation of these antiproliferative drugs may extend the intravitreal half-life and increase their efficacy. METHODS: The current study evaluated the pharmacokinetic behavior of intravitreally injected 5-fluorouridine (5-FUR), free and encapsulated in liposomes, either conventionally or coated with collagen into 25 New Zealand rabbits. Additionally, we investigated the retinal toxicity of intravitreal injections of 100, 250 and 500 microg as well as 1 mg 5-FUR as free drug or encapsulated in liposomes in the rabbit eye. RESULTS: The half-life of free 5-FUR after liposome injection into the vitreous cavity was 18.17+/-2.43 h, considerably longer than the half-life of free 5-FUR (0.82 h). Electrophysiologic tests did not show any changes in latency and a-wave amplitude and minimal changes in the b-wave amplitude. Histopathologic studies revealed integrity of the inner limiting membrane, and mild vacuolization in the outer retina. CONCLUSION: Encapsulation of 5-FUR within liposomes markedly increases its intravitreal half-life. Our study suggests that liposome-encapsulated 5-FUR is not toxic to the retina even at doses of 1 mg.
