St John's wort modulation and developmental expression of multidrug transporters in the rat

Abstract

Extracts of St John's wort (SJW) (Hypericum perforatum) are a potent inducer of enzymes of the cytochrome P450 system and of the transport protein P-glycoprotein, and interactions with a range of commonly prescribed medications have been described. In addition, recent experimental data suggest that, this otherwise safe treatment, could have some side effects when consumed during pregnancy and lactation. The aim of this study was to investigate, in Wistar rats, the effect of a treatment with high doses of SJW extract (100 and 1000 mg/kg/day) administered prenatally and during breastfeeding, on the level of transcripts of mdr1a, mdr1b, mrp1, mrp2 and cyp3A2 genes. All transcripts were detected in the liver, and their level of expression increased from fetuses to adults. SJW administration, at both dosages, caused a significant decrease of the levels of mdr1a, mdr1b, mrp1 and mrp2 in the livers of fetuses, and an increase in the levels of mdr1a, mdr1b, mrp2 and cyp3A2 in the mothers. In the other organs examined, a physiological regulation during ontogenesis was also evident, but SJW administration did not modify the expression level of the considered transcripts. These data suggest that the administration of the extract together with drugs that are substrates of transport proteins could be particularly hazardous during pregnancy.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…The ontogeny of Mdr1a and -1b in mouse kidneys corresponds with increased renal excretion of the Pgp substrate, digoxin, from postnatal days 0 to 21 (Pinto et al, 2005). Similar maturation of Mdr1a, Mdr1b, and Mrp2 mRNA in rat kidneys occurs postnatally (Rosati et al, 2003;Garrovo et al, 2006).…”

“…From gestation through adulthood, there are increases in the mRNA expression of rodent Mdr1a, Mdr1b, and Mrp2 in brain (Rosati et al, 2003;Garrovo et al, 2006;Cui et al, 2009c). Pgp protein reaches adult levels in mouse brain by 21 days .…”

“…It was recently shown that human Pgp protein can be detected on microvessel endothelial cells of the brain as early as 22 weeks of gestation, and staining intensity increases with development (Daood et al, 2008). Conversely, Mrp1 mRNA is similar in the rat fetal, newborn, and adult brain (Garrovo et al, 2006). Human MRP1 protein staining in the choroid plexus and ventricular ependyma is observed early in development (Daood et al, 2008).…”

Regulation of hepatic ABCC transporters by xenobiotics and in disease states

“…During development, in Sprague-Dawley (SD) rats, Mrp1 mRNA levels decrease gradually from birth to the adult liver (de Zwart et al, 2008). However, in the Wistar rat liver, Mrp1 transcripts expression does not change from the fetal to adult liver (Rosati et al, 2003; Garrovo et al, 2006), while it decreases significantly in aging rats (Rosati et al, 2003). During pregnancy, in SD rats, liver Mrp1 mRNA and protein are not altered at gestational days 20–21 (Cao et al, 2002).…”

Drug—Botanical Interactions: A Review of the Laboratory, Animal, and Human Data for 8 Common Botanicals

“…[191][192][193][194] Interestingly, a study conducted in pregnant Wistar rats indicates that St John's wort decreases hepatic drug transport proteins (Pgp and MRP2) and CYP3A enzymes in the pups and increases these proteins in the mothers. 195 Therefore, age may affect the dominance of St John's wort on Pgp and CYP3A. The constituents responsible for inducing CYP3A and Pgp are hyperforin, although other constituents, including hypericin and the flavonoids, may also contribute to the effects reported in the literature.…”