Blockade of CYP1A2 produced an unknown potential hepatotoxic molecule through FLU-1, and GSH might play an important role in diminishing the reactive hepatotoxic metabolite.
ABSTRACT:Flutamide is used for prostate cancer therapy but occasionally induces severe liver injury. Flutamide is hydrolyzed in the body into 5-amino-2-nitrobenzotrifluoride (FLU-1) and then further oxidized. In our previous study, N-hydroxy FLU-1 (FLU-1 N-OH) was detected in the urine of patients and exhibited cytotoxicity in rat primary hepatocytes. In the present study, we have assessed the roles of FLU-1 N-oxidation and hepatic glutathione (GSH) depletion in liver injury. FLU-1 (200 mg/kg p.o.) was administered to C57BL/6 mice for 5 days together with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) (3 mg/kg i.p.) for the first 3 days. Mice were fasted for the last 2 days to deplete hepatic GSH. Administration of FLU-1 alone did not affect serum alanine aminotransferase activities (ALT), whereas coadministration of FLU-1 and TCPOBOP significantly increased ALT in fasted mice but not in nonfasted mice.Microsomal FLU-1 N-hydroxylation was enhanced approximately 5 times by TCPOBOP treatment. Flutamide metabolite-protein adducts were detected in liver microsomes incubated with FLU-1 N-OH, but not with FLU-1 and flutamide, by immunoblotting using antiflutamide antiserum. In the presence of mouse liver cytosol, FLU-1 N-OH was reduced back into FLU-1. This enzymatic reduction required NAD(P)H as a cofactor. The reduction was enhanced by the coexistence of NAD(P)H and GSH, whereas it was markedly inhibited by allopurinol (20 M). By using purified bovine xanthine oxidase, the reduction was observed in the presence of NAD(P)H. These results suggest that FLU-1 N-OH is involved in flutamideinduced hepatotoxicity and that cytosolic reduction of FLU-1 N-OH plays a major role in protection against flutamide-induced hepatotoxicity.
-Drug-induced hepatotoxicity is a common reason for discontinuing the development of candidate clinical drugs. In the present study, we investigated the utility of three-dimensionally cultured human hepatocytes (spheroids) for prediction of hepatotoxicity, using a panel of model drugs: acetaminophen, benzbromarone, chlorpromazine, cyclosporin A, diclofenac, fialuridine, flutamide, imipramine, isoniazid, ticlopidine and troglitazone. Cultured spheroids showed a significant increase of albumin secretion from 2 to 7 days; the secretion started to decrease at 14 days, but continued from 14 days to 21 days. The morphology of the spheroids was well maintained for 21 days. Long-term exposure of spheroids to hepatotoxic drugs resulted in concentration-dependent depression of albumin secretion and elevation of aspartate aminotransferase (AST) leakage. The estimated 50% effective concentration (IC 50 ) values for decrease of albumin secretion changed from 7 days to 14 days, but similar values were obtained at 14 and 21 days, except for diclofenac. Since the IC 50 values and the values of drug concentration inducing 1.2-fold elevation of AST leakage (F1.2) were similar at 14 and 21 days, an incubation period of 14 days was
In our previous rodent studies, the paclitaxel (PTX)-incorporating polymeric micellar nanoparticle formulation NK105 had showed significantly stronger antitumor effects and reduced peripheral neurotoxicity than PTX dissolved in Cremophor ® EL and ethanol (PTX/CRE). Thus, to elucidate the mechanisms underlying reduced peripheral neurotoxicity due to NK105, we performed pharmacokinetic analyses of NK105 and PTX/CRE in rats. Among neural tissues, the highest PTX concentrations were found in the dorsal root ganglion (DRG). Moreover, exposure of DRG to PTX ( C max_PTX and AUC 0-inf._PTX ) in the NK105 group was almost half that in the PTX/CRE group, whereas exposure of sciatic and sural nerves was greater in the NK105 group than in the PTX/CRE group. In histopathological analyses, damage to DRG and both peripheral nerves was less in the NK105 group than in the PTX/CRE group. The consistency of these pharmacokinetic and histopathological data suggests that high levels of PTX in the DRG play an important role in the induction of peripheral neurotoxicity, and reduced distribution of PTX to the DRG of NK105-treated rats limits the ensuing peripheral neurotoxicity. In further analyses of PTX distribution to the DRG, Evans blue (Eb) was injected with BODIPY ® -labeled NK105 into rats, and Eb fluorescence was observed only in the DRG. Following injection, most Eb dye bound to albumin particles of ~8 nm and had penetrated the DRG. In contrast, BODIPY ® –NK105 particles of ~90 nm were not found in the DRG, suggesting differential penetration based on particle size. Because PTX also circulates as PTX–albumin particles of ~8 nm following injection of PTX/CRE, reduced peripheral neurotoxicity of NK105 may reflect exclusion from the DRG due to particle size, leading to reduced PTX levels in rat DRG (275).
NK012 is a micelle-forming macromolecular prodrug of 7-ethyl-10-hydroxy camptothecin , an active metabolite of irinotecan. It is accumulated and retained in tumor tissues and gradually releases SN-38 in an enzyme-independent manner. NK012 was previously demonstrated to have stronger antitumor activity than irinotecan in a broad range of human solidtumor xenograft models. In our study, we used an orthotopic multiple myeloma (MM) model created by injecting CD138-positive U266B1, a myeloma cell line that produces human IgE lambda light chain (monoclonal protein, M protein), into immunodeficient NOD/Shi-scid, IL-2Rc c null mice. This model shows typical bone marrow infiltration by the human myeloma cells.We evaluated the antimyeloma activity of intravenously administered NK012 in this model and showed that it suppressed the M protein concentration in the plasma and proliferation of myeloma cells in the bone marrow in a dose-dependent manner. NK012 suppressed the progression of hind-leg paralysis and prolonged the survival time of the mice compared to the untreated control group. In combination with bortezomib (BTZ), NK012 increased the median survival time compared to that with BTZ alone. In conclusion, these results suggest that NK012 is a potential candidate for use-alone and in combinationin the treatment of MM in humans.
Six zymograms were compared for extracts of muscle-stage larvae of the seven Trichinella isolates, using isoelectric focusing in polyacrylamide gels. The isozyme patterns of acid phosphatase among them fell into four types. T. pseudospiralis from a raccoon and the Polar strain from a polar bear formed type 1 and type 2, respectively. The Iwasaki strain from a Japanese black bear and the Yamagata strain from a raccoon dog, both from Japan, were type 3. Type 4 consisted of three remaining strains, viz. the Polish strain from a wild pig, the USA strain from a pig, and the Thai strain from a human case, all of which have similar infectivity to pigs. The isozyme patterns of esterase 1, beta-N-acetylglucosaminidase, and peptidase were similar in types 2 and 3. Those of esterase D were common to types 2-4 but not to type 1. In the zymogram of mannosephosphate isomerase, types 2-4 but not type 1 had one common band, whereas in the other bands type 2 was markedly distinguished from types 3 and 4. In the present study, the molecular phylogenic tree was constructed for the first time on the basis of our present and previous electrophoretic data by the use of cluster analysis, and the evolutionary process was considered as follows: T. pseudospiralis (type 1) and T. spiralis (the common ancestor of types 2-4) were initially separated. Next, the common ancestor of the strains from wild carnivores (types 2 and 3) and type 4 were separated. Finally, the Polar strain (type 2) and the Japanese strain (type 3) were separated.
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