Emodin-induced hepatotoxicity was exacerbated by probenecid through inhibiting UGTs and MRP2.

Aggravating effect of probenecid (a traditional anti-gout agent) on emodin-induced hepatotoxicity was evaluated in this study. 33.3% rats died in combination group, while no death was observed in rats treated with emodin alone or probenecid alone, indicating that emodin-induced (150 mg/kg) hepatotoxicity was exacerbated by probenecid (100 mg/kg). In toxicokinetics-toxicodynamics (TK-TD) study, aspartate aminotransferase (AST) and systemic exposure (area under the serum concentration-time curve, AUC) of emodin and its glucuronide were significantly increased in rats after co-administrated with emodin and probenecid for 28 consecutive days. Results showed that the increased AUC (increased by 85.9%) of emodin was mainly caused by the decreased enzyme activity of UDP-glucuronosyltransferases (UGTs, decreased by 11.8%-58.1%). In addition, AUC of emodin glucuronide was increased 5-fold, which was attributed to the decrease of multidrug-resistant-protein 2 (MRP2) protein levels (decreased by 54.4%). Similarly, in vitro experiments proved that probenecid reduced the cell viability of emodin-treated HepG2 cells through inhibiting UGT1A9, UGT2B7 and MRP2. Our findings demonstrated that emodin-induced hepatoxicity was exacerbated by probenecid through inhibition of UGTs and MRP2 in vivo and in vitro, indicating that gout patients should avoid taking emodin-containing preparations in combination with probenecid for a long time.

Suplementación con antioxidantes no previene nefrotoxicidad por cisplatino en pacientes con cáncer cérvico uterino avanzado / Anti oxidant agent does not prevent nefro-toxicity in advance cervical cancer patients

En México el cáncer cérvico uterino al igual que en otros países de América representa un grave problema de salud pública. El tratamiento depende de su extensión; los estadios localmente avanzados son tratados con una combinación de quimioterapia con cisplatino y radioterapia. Ambas terapias utilizadas son consideradas oxidativas y por ello son capaces de influir en las toxicidades del propio tratamiento, el objetivo de este trabajo es determinar la eficacia de la suplementación con antioxidantes y su efecto sobre la prevención de la toxicidad renal por cisplatino. Ensayo clínico aleatorizado que incluyó a pacientes con cáncer cérvico uterino en estadios localmente avanzados cuyo tratamiento antineoplásico consistió en radioterapia y quimioterapia con cisplatino. Se asignó aleatoriamente a las pacientes a recibir un suplemento antioxidante diariamente o bien un placebo. Se determinó la función renal mediante la depuración de creatinina antes de iniciar el tratamiento y al término del mismo. Se realizaron pruebas t-Student inter e intra grupales a fin de determinar el efecto de la suplementación sobre los parámetros evaluados. No se encontraron diferencias estadísticamente significativas entre ambos grupos; en cambio, existió una disminución significativa en ambos grupos al finalizar el tratamiento. La suplementación con antioxidantes no es capaz de prevenir la toxicidad a nivel renal producida por la quimioterapia con cisplatino.

In Mexico, our country, the pathology of cervical cancer is a major public health issue, the same situation is present in other American countries. The treatment for this pathology depends on its extension; for locally advanced stages, a combination of radiotherapy and chemotherapy with cisplatin drug is common used. The both therapies are considered to be pro oxidative and this can be implied in the toxicities of the treatment. The objective of this work was to determine the efficacy of antioxidant supplementation on the prevention of cisplatin drug in the renal toxicity. We conducted a randomized clinical trial in the patients with locally advanced stage cervical cancer whose antineoplastic treatment consisted in radiation therapy and chemotherapy with the cisplatin drug. The patients were randomly assigned to receive either an antioxidant supplement or the placebo. We assessed renal function as creatinine clearance before and after concluding the oncologic treatment. We performed inter and intragroupal t-Student tests in order to determine the effect of the antioxidant supplementation on the evaluated parameters. No statistically significant differences we were found between the groups; however, there was a significant decrease in renal function in the both groups after finalizing the oncologic treatment. The antioxidant supplementation does not prevent the renal toxicity from the cisplatin drug chemotherapy.

The nephrotoxicity and hepatotoxicity of 1,1,2,2-tetrafluoroethyl-L-cysteine in the rat.

Recent studies have shown that tetrafluoroethylene is a renal and hepatic carcinogen in the rat. In this study, we have examined the ability of a single i.p. dose of 1,1,2,2-tetrafluoroethyl-L-cysteine (TFEC), a major metabolite of tetrafluoroethylene, to produce hepatic and renal injury in male and female rats. We have also examined the effect of blocking the renal organic anion transport system with probenecid and of inhibiting the activity of cysteine conjugate beta-lyase with aminooxyacetic acid on the extent of renal injury produced by TFEC. Doses of > or = 12.5 mg/kg TFEC produced renal tubular necrosis to the pars recta of the proximal tubules within 24 h in both male and female rats. This was associated with an increased kidney to body weight ratio and plasma urea at doses of > or = 25 mg/kg. No consistent evidence of liver injury was seen at doses up to 50 mg/kg TFEC in rats of either sex, although occasional vacuolation of hepatocytes and a small dose-related increase in liver to body weight ratio was observed. Prior treatment of female rats with probenecid completely prevented the renal injury produced by either 25 or 50 mg/kg TFEC as judged by plasma urea and histopathology. However, prior treatment of female rats with aminooxyacetic acid afforded no protection against the nephrotoxicity produced by either TFEC or the cysteine conjugate of hexachloro-1,3-butadiene. Thus no major sex difference in nephrotoxicity in the rat was seen with TFEC, while accumulation of TFEC, or its N-acetyl derived metabolite, into renal proximal tubular cells via a probenecid sensitive transport system appears to be a key event in the mechanism of nephrotoxicity. The lack of protection observed with the cysteine conjugate beta-lyase inhibitor, aminooxyacetic acid, may reflect the inability to completely inhibit the mitochondrial form of this enzyme and thereby prevent the formation of the reactive metabolite. Our acute studies provide no insight concerning the liver carcinogenicity of tetrafluoroethylene.