Precision toxicology shows that troxerutin alleviates ochratoxin A-induced renal lipotoxicity.

Lipotoxicity is the most common cause of severe kidney disease, with few treatment options available today. Precision toxicology can improve detection of subtle intracellular changes in response to exogenous substrates; thus, it facilitates in-depth research on bioactive molecules that may interfere with the onset of certain diseases. In the current study, troxerutin significantly relieved nephrotoxicity, increased endurance, and improved systemic energy metabolism and renal inflammation in OTA-induced nephrotic mice. Lipidomics showed that troxerutin effectively reduced the levels of triglycerides, phosphatidylcholines, and phosphatidylethanolamines in nephropathy. The mechanism was partly attributable to troxerutin in alleviating the aberrantly up-regulated expression of sphingomyelinase, the cystic fibrosis transmembrane conductance regulator, and chloride channel 2. Renal tubular epithelial cells, the main site of toxin-induced accumulation of lipids in the kidney, were subjected to transcriptomic profiling, which uncovered several metabolic factors relevant to aberrant lipid and lipoprotein metabolism. Our work provides new insights into the molecular features of toxin-induced lipotoxicity in renal tubular epithelial cells in vivo and demonstrates the function of troxerutin in alleviating OTA-induced nephrosis and associated systemic energy metabolism disorders.-Yang, X., Xu, W., Huang, K., Zhang, B., Wang, H., Zhang, X., Gong, L., Luo, Y., He, X. Precision toxicology shows that troxerutin alleviates ochratoxin A-induced renal lipotoxicity.

Toxicity of venalot (a mixture of coumarin and troxerutin) in the baboon.

Venalot, a mixture of coumarin and troxerutin, in the proportion 1 to 6 respectively, was given orally to baboons at dosages of 0, 100, 300 and 1000 mg/kg/day for 26 weeks. Vomiting, usually within 3 h of administration and considered to be of central origin, in addition to vomiting immediately after dosing, was noted in animals receiving 1000 mg/kg/day. At this level, collapse on several occasions in two animals, one of which died, was also observed. Another animal receiving 1000 mg/kg/day was killed for humane reasons following a period of weight loss, reduced appetite and deterioration in body condition. However, no adverse effect on body weight gain, food or water consumption, ophthalmoscopic or electrocardiographic examinations were noted in any other animals during this study. Increased levels of liver function (serum leucine amino-peptidase (LAP), and serum ornithine carbamyl transferase (OCT) were noted during the dosing period, together with slightly increased liver weights terminally for animals receiving 1000 mg/kg/day; however, as no morphological or ultrastructural changes were noted, these findings were considered to be attributable to hypertrophy.

Teratogenic effect of hydroxyethylrutoside, a flavonoid derivate drug--a population-based case-control study.

OBJECTIVE: Hydroxyethylrutoside (HER), a flavonoid derivate drug, used frequently in pregnant women for the treatment of vascular diseases. The aim of this case-control study was to evaluate the teratogenic potential of oral HER treatment in the population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities. METHODS: Comparative analysis of exposure (HER treatment) during pregnancy in the mothers of cases with congenital abnormalities and matched control newborns without any defect in the population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities. RESULTS: Of the 22,843 cases with congenital abnormalities, 567 (2.5%) had mothers with HER treatment while of 38,151 matched controls, 1143 (3.0%) were born to mothers with HER treatment (OR with 95% CI: 0.8, 0.7-0.9). However, an association of HER treatment during the second and/or third month of pregnancy was found with the higher risk of unilateral ocular coloboma (OR with 95% CI: 5.4, 2.2-12.9) and a new congenital abnormality syndrome including anotia/microtia, poly/syndactyly and caudal (genital and anal) defects (OR with 95% CI: 3.0, 1.3-27.4). CONCLUSIONS: Oral HER treatment during early pregnancy associates with a higher risk for ocular coloboma and for a newly delineated congenital abnormality syndrome.

[Light and electron microscopic studies on the dose and time dependency of the hepatotoxicity of benzopyrones]. / Licht- und elektronenmikroskopische Untersuchungen zur Hepatotoxizität von Benzopyronen in Abhängigkeit von Dosis und Anwendungsdauer.

Both male and female Wistar rats were treated with daily oral doses of a combination of the active components coumarin and troxerutin (Venalot-Depot) corresponding to 1, 8, 64 and 128 mg coumarin/kg b.w., respectively. Goal of the study was to study coumarin at the target organ liver for a longer period, after it had turned out from a fertility and teratogenicity study that liver alterations were observed in the P-generation following the elevated doses' treatment up to 10 weeks (male) and 3 weeks (female). Light and electron microscopic examinations of the livers revealed the following findings: The lesions are dose- and time-dependent. First signs of coumarin-induced hepatocellular alterations are fine granular protein-like precipitations in the region of the sER (smooth endoplasmatic reticulum) which conflux to large areas. The glycogen content decreases significantly at the same time. This is followed by an osmotically controlled water redistribution in the cytoplasm and an increased water inflow from the extracellular space (vacuolar degeneration) as well as an overload of the cytoplasm with lipids, taken in by nutrition. Doses of 64 and 128 mg/kg b.w. of the test substance produced extensive hepatic alterations, associated with hypertrophy of the liver, with a focal onset in the globular periphery, subsequently extending to peripheral and intermediate lobular areas. Since light or electron microscopic alterations were not observed following doses of 1 and 8 mg/kg b.w., the dose of 8 mg coumarin/kg b.w. can be determined as no effect dose for the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

[Reproduction toxicologic studies on rats following oral administration of benzopyrone preparations]. / Reproduktionstoxikologische Untersuchungen an Ratten nach oraler Verabreichung eines Benzopyron-Präparates.

The influence of the benzopyrone preparation Venalot (active substances: coumarin and troxerutin; in the following briefly called CT) on the fertility and teratogenicity as well as on the perinatal and postnatal development of a total of 3 generations was evaluated in a combined study. The 1-, 8-, 64-, and 128fold of the daily therapeutical doses for humans was suspended in tap water and administered orally by gavage to 95 male and 190 female SPF rats (Wistar) (test groups 2 to 5). 23 male and 46 female rats (test group 1) served as controls and were given tap water alone. The male animals were subjected to a pretreatment of 10, the female animals to one of 3 weeks. The treatment was continued during the phase of mating. The animals scheduled for cesarian section received the test substance until the day of the laparatomy (gestation day 20), those selected for littering throughout lactation (day 24 post partum). With the aid of a stepwise histological technique, the teratological examination could also disclose non lethal malformations of the organs. The treatment resulted in a decreased food consumption in the animals of group 5 and in a reduced gain of body weight as well as pathologic-anatomically and histologically demonstrable, definitely dose related hepatic lesions. The test substance had no effect on either the treated P generation nor the untreated F1 generation. As teratogenic effects could also not be demonstrated and the peri- and postnatal development of the filial generations 1 and 2 was undisturbed, the present study does not indicate a reproduction toxicological risk.(ABSTRACT TRUNCATED AT 250 WORDS)