• BMB Reports
• /
• v.44 no.7
• /
• pp.423-434
• /
• 2011

A female hormone, estrogen, is linked to breast cancer incidence. Estrogens undergo phase I and II metabolism by which they are biotransformed into genotoxic catechol estrogen metabolites and conjugate metabolites are produced for excretion or accumulation. The molecular mechanisms underlying estrogen-mediated mammary carcinogenesis remain unclear. Cell proliferation through activation of estrogen receptor (ER) by its agonist ligands and is clearly considered as one of carcinogenic mechanisms. Recent studies have proposed that reactive oxygen species generated from estrogen or estrogen metabolites are attributed to genotoxic effects and signal transduction through influencing redox sensitive transcription factors resulting in cell transformation, cell cycle, migration, and invasion of the breast cancer. Conjuguation metabolic pathway is thought to protect cells from genotoxic and cytotoxic effects by catechol estrogen metabolites. However, methoxylated catechol estrogens have been shown to induce ER-mediated signaling pathways, implying that conjugation is not a simply detoxification pathway. Dual action of catechol estrogen metabolites in mammary carcinogenesis as the ER-signaling molecules and chemical carcinogen will be discussed in this review.

• Korean Journal of Environmental Agriculture
• /
• v.13 no.3
• /
• pp.271-278
• /
• 1994

Mode of safening action of N-(4-chlorophenyl)maleimide (CPMI) on metolachlor [2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-l-methylethyl) acetamide] was investigated in sorghum(Sorghum bicolor L.). CPMI was synthesized by dehydration of N-(4-chlorophenyl)maleamic acid (CPMA) which was obtained from amination with maleic anhydride and 4-chloroaniline. Melting points of CPMA and CPMI (>95% purity) were $200-202^{\circ}C$ and $116-118^{\circ}C$, respectively. Growth response study indicated that seed treatment of CPMI increased tolerance of sorghum shoot to metolachlor approximately threefold. Sorghum shoot was more sensitive to injury caused by metolachlor and CPMI activity than the root. Metolachlor was initially absorbed by sorghum shoot and metabolized to the metolachlor-glutathione conjugate in CPMI-untreated and treated shoots. However, CPMI treatment significantly accelerated metabolism of $[^{14}C]$metolachlor in sorghum shoot, resulting in decrease in metolachlor content and increase in formation of the glutathione conjugate. It was concluded that the protection against metolachlor injury conferred by CPMI appeared to be correlated to detoxification of metolachlor in sorghum shoot tissue.

• Biomolecules & Therapeutics
• /
• v.11 no.3
• /
• pp.163-168
• /
• 2003

Pharmacokinetics of eupatilin (an active components of $Stillen^{\circledR}$, a new antigastritic agent) were investigated after both intravenous and oral administration at a dose of 30mg/kg to rats. After intravenous administration, the plasma concentrations of unchanged eupatilin declined rapidly with a mean terminal half-life of 0.101 h. Eupatilin was eliminated fast in rats; the total body clearance was 121 mL/min/kg. Eupatilin was mainly metabolized in rats; the percentage of intravenous dose of eupatilin excreted in 24 h urine and feces as unchanged eupatilin was only 2.5 and 0.919％, respectively. Eupatilin was mainly metabolized to form its glucuronide conjugate; after intravenous administration, 15.9 and 51.7％ of intravenous dose was excreted in 24 h urine and feces, respectively, as eupatilin plus its glucuronide. After oral administration, the absolute bioavailability was only 3.86％ based on $AUC_{0-24h}$ of eupatilin plus its glucuronide. Approximately 68.5％ of oral dose was not absorbed from the entire gastrointestinal tract. Therefore, it could be concluded that the superior effect of eupatilin in experimental animal models of gastric ulcer and inflammatory bowel disease after oral administration could be due to the local action of eupatilin. Further pharmacokinetic studies to elucidate the local action of eupatilin are required.

• Korean Journal of Weed Science
• /
• v.18 no.2
• /
• pp.161-170
• /
• 1998

Antagonistic mode of action of fenoxaprop-P-ethyl [ethyl(R)2-4-{(6-chloro-2-benzoxazolyloxy) phenoxy}propionate] with bentazon was investigated with respect to absorption, translocation, metabolism, and change in target site response of fenoxaprop-P-ethyl using four-leaf stage of rice(Oryza sativa L.) and barnyardgrass [Echinochloa eras-galli (L.) P. Beauv.]. Shoots of rice and barnyardgrass was more sensitive to fenoxaprop-P-ethyl than the roots. More than 90% of fenoxaprop-P-ethyl was absorbed within 6 hours after treatment and 30% of the absorbed was acropetally and basipetally translocated at 24 hours after treatment. Fenoxaprop-P-ethyl was rapidly transformed to its acid form, fenoxaprop(2-[4-(6-chloro-2-benzoxazolyloxy)phenoxy]propionic acid), which was subsequently metabolized to polar conjugates. However, changes in absorption, translocation, and metabolism of fenoxaprop-P-ethyl by bentazon treatment were not found in both species. Background activity of acetyl-CoA carboxylase(ACCase) in rice and barnyardgrass was 26.5 and 23.2nmol/min/mg, respectively. Concentration required to inhibit fifty percent enzyme activity$(I_{50})$ in vitro was 6.5~7.4${\mu}M$ of fenoxaprop-P-ethyl and more than 500${\mu}M$ of bentazon. There were no significant differences in $I_{50}$ value between two treatments of fenoxaprop-P-ethyl alone and its bentazon mixture. However, bentazon reduced ACCase activity in vivo and inhibited electron transport in chloroplast thylakoid. Based on the results obtained, it is concluded that the antagonistic effect of bentazon occurs due not to direct effect on target site of fenoxaprop-P-ethyl, but to indirect involvement in reducing herbicidal activity of fenoxaprop-P-ethyl through physiological disturbances caused by bentazone at whole chloroplast level.

• Toxicological Research
• /
• v.3 no.2
• /
• pp.129-141
• /
• 1987

Hepatocytes isolated from rats which have been pretreated with phenobarbital (80 mg/kg for 3 days), were able to take up N-acetylcysteine from surrounding medium and were able to synthesize the reduced glutathione ($GSH^{\ast}-3$) intracellularly. The N-acetylcysteine is quickly deacetylated after the uptake and increases the pool size of cysteine, which was very low initially (5 nmol/$10^6$ cells). From this increased intracellular cysteine pool, GSH was synthesized. Freshly isolated rat hepatocytes contained a high level of GSH (30 nmol/$10^6$ cells), but upon incubation with the diethylmaleate, it was markedly decreased (10 nmol/$10^6$ cells). The hepatocytes with depleted GSH have lost viability upon incubations with acetaminophen (5mM) and paraquat (2 mM). However, when the N-acetylcysteine (1 mM) was added to this incubation condition, these chemical induced hepatocellular necrosis were prevented for longer durations. This N-acetylcysteine dependent protective effect against the hepatotoxic chemicals was lost by adding methionine sulfoximine (10 mM), an inhibitor of GSH biosynthesis. Both the carbontetrachloride (5 mM) and chioroform (5 mM) added to the incubation medium caused rapid losses of GSH and cell viability, even without the prior depletion of cellular GSH. However, again, if the 1mM N-acetylcysteine was supplemented, the rates of losses of GSH and cell viability were retarded in both cases. Even though large amounts of the added N-acetylcysteine was present in the cell, N-acetylcysteine conjugate of acetaminophen was not formed. Instead, only large amounts of GSH conjugate of the drug was produced. Thus, it is concluded that the added N-acetylcysteine is taken up and utilized for resynthesis of GSH. In turn, this resynthesized GSH contributes to the protection against cytotoxicity inducible with hepatotoxic drugs.

• Animal cells and systems
• /
• v.5 no.1
• /
• pp.51-57
• /
• 2001

We have previously shown that oocyte maturation is induced by an immobilized progesterone, progesterone-3-carboxymethyloxime - bovine serum albumin conjugate (P-BSA) in Rana dybowskii. In this study, we confirmed the maturation inducing activity of P-BSA on Xenopus oocyte and examined the binding character of the immobilized progesterone on the surface of Xenopus oocytes after removal of the vitelline layer. P-BSA induced maturation of Xenopus oocytes but E-BSA failed to do so as observed in Rana. Binding of the immobilized progesterone, fluorescein isothiocyanate-labeled progesterone-3-0-carboxymethyloxime-BSA (P-BSA-FITC) on the devitellined oocytes surface was examined by fluorescence confocal microscopy. The binding affinity of P-BSA-FITC to the devitellined oocyte was higher than that of estrogen-BSA-FITC (E-BSA-FITC) or testosterone-BSA-FITC (T-BSA-FITC). The binding disappeared in the presence of excess free progesterone but not in the presence of free estrogen. Maximum binding occurred after two-hours of incubation with P-BSA-FITC at pH 7.5. Stronger binding occurred in oocytes at stage Vl than stage IV, and in vitro treatment of hCG enhanced the binding. Taken together, these results suggest that a specific receptor for progesterone exists on the plasma membrane of Xenopus oocytes and that progesterone acts initially on this putative receptors and triggers generation of membrane-mediated second messengers during the early stage of oocyte maturation In amphibians.

• Korean Journal of Weed Science
• /
• v.15 no.4
• /
• pp.247-253
• /
• 1995

The herbicide butachlor [N-(butoxymethyl)-2-chloro-N-(2,6-di-methylphenyl) acetamide] is widely used by farmers as a tool for weed management of transplanted rice(Oryza sativa L.) in Taiwan. The herbicide did not stop germination of rice and weed seeds, but strongly inhibited the subsequent growth of young shoots and roots. The inhibition was also strong on established seedlings. However, they could recover to normal growth after the herbicide effect disappeared. Butachlor greatly decreased the endogenous indole-3-acetic acid (IAA) but increased the endogenous abscisic acid (ABA) contents of rice seedlings. Addition of lAA into growth medium (Hoagland's solution) partly relieved growth inhibition. Pretreatment of both gibberellic acid ($GA_3$) and IAA 24 hours before butachlor treatment almost completely alleviated the butachlor-interfere with GA and/or IAA metabolism or their action resulting in the growth inhibition of rice. Butachlor was readily absorbed by rice roots. During 24 hours of uptake experiment, 32% of the applied herbicide was absorbed. Pretreatment of the herbicide for 2 days did ncx affect the absorption. Of the absorbed herbicide, 80% remained in roots, only 20% transported into shoots, and more than 50% was metabolized to water soluble substances. Thin-layer chromatographic (TLC) analysis indicated that the Rf value of the most abundant metabolite was butachlor-glutathione conjugate. Rice, barnyardgrass (Echinochloa crus-galli (L.) Beauv.), and monochoria (Monochoria vaginalis Presl) seedlings contained relatively high level of non-protein thiols, while the glutathione S-transferase (GST) activity was found highest in rice, barnyardgrass the next, monochoria the lowest. The difference in GST activity among these species might be related to their sensitivity to butachlor.