Changes in hepatic metabolic enzyme activities and biliary excretion of 4-nitrophenol in streptozotocin induced diabetic rats

Abstract Activity of hepatic metabolic enzymes of glucuronidation and sulfation of 4-nitrophenol (PNP) and biliary excretion of its glucuronide (PNP-G) and sulfate (PNP-S) conjugates have been investigated in control and streptozotocin (STZ)-induced diabetic rats. 500 µM PNP solution was luminally perfused in a cannulated jejunal loop for 90 minutes. It was found that biliary excretion of PNP-G was significantly decreased in the diabetic rats. This effect of STZ could be completely reversed by administration of rapid-acting insulin. Activity of hepatic UDP-glucuronyltransferase and ß-glucuronidase was also depressed by the STZ pretreatment. Administration of insulin antagonized the inhibitory action of STZ on UDP-glucuronyltransferase, but the reduced activity of ß-glucuronidase was not reversed. Biliary excretion of PNP-S was also depressed in the diabetic rats. Whereas, different effects of insulin administration were observed. Namely, the lower biliary excretion rate of PNP-S was not changed after administration of insulin. Activity of the sulfotransferase and the arylsulfatase enzymes was not altered either by STZ pretreatment or by insulin administration. Biliary excretion of PNP was also significantly depressed by STZ and this depression was not changed after insulin administration. The results call attention to hepatobiliary circulation of low molecular weight xenobiotics and their glucuronide and sulfate conjugates

Bases moleculares de la función excretora de tipo hepatobiliar de la placenta / Molecular basis of excretory function placental hepatobiliary type

The liver plays an important excretory role eliminating from the body potentially toxic compounds that are xenobiotics or produced endogenously, such as bile acids and biliary pigments. This involves both transport and biotransformation processes. During intrauterine life, the inmature fetal liver cannot carry out this function. Therefore, the placenta performs a hepatobiliary-like excretory role, transferring cholephilic compounds from the fetus to the mother. The similarity of this function in the placenta and the adult liver is probably accounted for by the presence in both organs of proteins of the OATP family, involved in the uptake of organic anions across the basolateral membrane of several epithelia, and of members of the superfamily of ATP-binding cassette (ABC) proteins, which are involved in the export of substances out of many different cells. Thus, several studies have shown that, in addition to a difussional component, that may become particularly important for unconjugated bilirubin, the main mechanisms for bile acids and bilirubin transplacental transfer from the fetus to the mother are carrier-mediated transport systems, which have vectorial properties and also play an important role in the placental barrier by preventing or reducing the net flux of noxious substances from the mother to the fetus.

El hígado juega un papel determinante en la excreción de sustancias potencialmente tóxicas de origen externo o producidas por el organismo, como ácidos biliares y bilirrubina. Esta función implica tanto procesos de transporte como de biotransformación. Durante la vida intrauterina, el hígado fetal no es aún capaz de realizar esta función, por lo que es la placenta la que asume un papel excretor similar al que desempeña el sistema hepatobiliar en el adulto. La similitud entre ambas funciones se debe a la presencia en ambos órganos de proteínas transportadoras de la familia OATP, que llevan a cabo la captación de aniones orgánicos en varios epitelios, y de miembros de la superfamilia de proteínas ABC ("ATP-binding cassette"), capaces de bombear al exterior celular una gran variedad de sustancias. Estudios recientes demostraron que, además de un componente difusional, que es más relevante en el caso de la bilirrubina no conjugada, la vía mayoritaria en la transferencia placentaria de ácidos biliares y bilirrubina está mediada por sistemas de transporte que, en conjunto, presentan características de vectorialidad feto-materna, y que por ello también juegan un papel en la barrera placentaria reduciendo el flujo de sustancias nocivas desde la madre al feto.