Mercapturic acid formation from lindane in rats

4-Chloro-, 2,4-dichloro-, 3,4-dichloro-, 2,3,5-trichloro-, and 2,4,5-trichlorophenylmercapturic acids were identified as main metabolites of lindane, γ-isomer of 1,2,3,4,5,6-hexachloro-cyclohexane, in rat urine. Pathways to these metabolites were shown to include $\text{(}\text{36}\text{45}\text{)-}\text{hexachlorocyclohexene}$ as the most important intermediary metabolite. $\text{(}\text{346}\text{5}\text{)-}\text{Pentachlorocyclohexene}$ and $\text{(}\text{346}\text{5}\text{)-}\text{tetrachlorocyclohexene}$ also seem to be involved in these pathways, while $\text{(}\text{36}\text{45}\text{)-}\text{pentachlorocyclohexene}$ plays a minor role in the pathway. Glutathione conjugation, using the rat liver soluble fraction, occurred directly on the polychlorocyclohexenes, not on their further transformed products. In in vivo biodegradation, $\text{(}\text{36}\text{45}\text{)-}\text{hexachlorocyclohexene}$ may be dechlorinated and dehydrochlorinated at the endoplasmic reticulum before it undergoes the glutathione conjugation in cytosol, although other polychlorocyclohexenes generally react in a manner similar to that in the in vitro reaction.     

CDAA inhibition of Kaurene oxidation in etiolated sorghum coleoptiles

N,N-Diallyl-2-chloroacetamide (CDAA) (0.25 ppmw; I μM) inhibited growth of 14-day-old sorghum (Sorghum bicolor (L) Moench. cv Funks G 522DR) when the herbicide was incorporated into sand. Kaurene oxidation was inhibited in a cell-free enzyme preparation from 4-day-old unruptured, etiolated coleoptiles. CDAA (1 μM) inhibited incorporation of [¹⁴C]mevalonic acid into kauren-19-oic acid (50%), with resultant increases in concentration of precursors. Thus, inhibition of gibberellin precursor biosynthesis was demonstrated, and this activity would explain many of the morphogenic and biochemical responses of grasses to CDAA.     

Absorption,metabolism and excretion of the fungicide triforine in the rat

Eighty per cent of orally administered triforine is absorbed by the rat. Maximum blood levels are reached 4 h after administration. After complete metabolic conversion has occurred, the fungicide absorbed is excreted mainly in the urine as a metabolite, N-[2,2,2-trichloro-1-(piperazin-1-yl)ethyl]formamide. Elimination is complete with most of the compound being excreted during the first 24 h following administration.     

The effect of CDAA (N,N,-diallyl-2-chloroacetamide) pretreatments on subsequent CDAA injury to corn (Zea mays L.)

The effects of CDAA (N,N-diallyl-2-chloroacetamide) pretreatment on subsequent CDAA injury to corn were examined and compared with the effects of the herbicide protectant R-25788 (N,N,-diallyl-2,2-dichloroacetamide). In addition, the effects of CDAA pretreatment on subsequent CDAA metabolism were determined. It was found that 5μM CDAA protected corn from injury by 200 μM CDAA when given as a 2.5- or 1-day pretreatment. R-25788 at similar concentrations did not protect corn from subsequent R-25788 injury. Pretreatment with CDAA increased GSH levels of corn roots by 61% within 1 day, and these levels did not increase with a longer 2.5-day pretreatment with CDAA. GSH-S-transferase activity was assayed spectrophotometrically using CDNB (1-chloro-2,4-dinitrobenzene). A 1-day pretreatment with CDAA increased the root GSH-S-transferase activity by 35%, but did not affect shoot GSH-S-transferase activity. A 2.5-day pretreatment resulted in a 50% increase in root GSH-S-transferase activity but no response of the shoot enzyme was observed. Even longer pretreatments with CDAA did not result in any further increases in enzyme activity. When corn roots pretreated with CDAA for 2.5 days were excised and incubated with radiolabeled CDAA, they exhibited greater rates of uptake and metabolism than did nonpretreated roots. With in vitro studies, a fairly high rate of nonenzymatic degradation of CDAA was observed. However, the enzymatic rate was always double that of the nonenzymatic rate under the experimental conditions used. It is concluded that elevations in the GSH levels and GSH-S-transferase activities of corn roots following CDAA pretreatments may be involved in the protection of corn from subsequent CDAA injury.     

Effects of EPTC, fluorodifen and monuron on transpiration and photosynthetic oxygen output in Eupatorium odoratum plants

The influence of foliar sprays of EPTC, fluorodifen and monuron on transpiration and photosynthetic oxygen output of Eupatorium odoratum plants is demonstrated. Foliar sprays with 100 ppm EPTC or monuron led to a significant decrease in transpiration for a continuous period of 14 days. Treatment with 100 ppm fluorodifen led to a noticeable increase in transpiration during the first eight days. All three herbicides significantly reduced photosynthetic oxygen output from the Eupaiorium plants. EPTC and monuron however, gave greatest effect. Reduction in transpiration from the plants was due to stomatal closure while reduction in photosynthetic oxygen output was due to both stomatal closure and probably also inhibition of the Hill reaction.     

Combined treatments of propachlor and trifluralin for weed control in cabbage

In four field experiments on a sandy loam, granular propachlor gave similar weed control to the wettable powder formulation but sometimes caused greater injury to drilled cabbage (Brassica oleracea L. var. capitata). Propachlor incorporated to 3 cm before drilling gave slightly poorer weed control than when surface-applied after drilling. A combination of 056 kg/ha trifluralin incorporated and 2·18 or 4·37 kg/ha propachlor after drilling gave better weed control than 1·12 kg/ha trifluralin or 4·37 kg/ha propachlor applied alone, and the marketable yields did not differ significantly from those of hand-weeded controls. When 4·37 kg/ha propachlor was incorporated with 0·56 kg/ha trifluralin before drilling the results were almost as good, and suggest that at suitable doses the two herbicides might be applied in one operation. Traitements combinés avec le propachlore et la trifluraline pour le désherbage du chou Dans quatre essais au champ sur un limon sableux, le propachlore granulé a donné un désherbage analogue à celui obtenu avec la formulation en poudre mouillable mais a provoqué parfois des dommages plus importants au chou cabus (Brassica oleracea L. var. capitata). Le propachlore incorporféà la profondeur de 3 cm avant le semis a eu un effet désherbant légérement plus faible qu'en traitement de surface aprés le semis. La combination d'une application de trifluraline incorporée à la dose de 0,56 kg/ha avec un traitement au propachlore aux doses de 2,18 et 4,37 kg/ha aprfès le semis, a donnféa une meilleure efficacité que 1,12 kg/ha de trifluraline ou 4,37 kg/ha de propachlore appliqués seuls, et les productions commercialisables n'ont pas été différentes de celles obtenues avec les témoins désherbés k la main. Lorsque le propachlore a été incorporé, à la dose de 4,37 kg/ha en association avec 0,56 kg/ha de trifluraline avant le semis, les résultats ont été presque aussi bons, ce qui suggère que à des doses convenables les deux herbicides peuvent être appliqués en une seule opération. Unkrautbekämpfung in Kohl mit kombinierten Behandlungen von Propachlor und Trifluralin In vier Feldversuchen auf sandigem Lehm wurde mit Propachlor-Granulat und Propachlor-Spritzpulver das Unkrautetwa gleieh gut bekämpft. Das Granulat verursaehte aber manchmal grossere Schäden bei gesätem Kohl (Brassica oleracea L. var. capitata). Wenn Propaehlor vor der Saat 3 cm tief eingearbeitet wurde, hatte man eine geringfugig schlechtere Unkräutbekampfung als bei Bodenbehandlung nach der Saat. Eine Kombination von 0,56 kg/ha Trifluralin (Einarbeitung) und 2,18 oder 4,37 kg/ha Propachlor nach der Saat, führte zu einer besseren Unkräutbekampfung als 1,12 kg/ha Trifluralin oder 4,37 kg/ha Propachlor alleine und die vermarktbaren Brnten entsprachen etwa denen der gejäteten Kontrollparzellen. Wenn 4,37 kg/ha Propachlor mit 056 kg/ha Trifluralin vor der Saat eingearbeitet wurden, waren die Ergebnisse fast genauso gut und lassen vermuten, dass bei entsprechenden Aufwandmengen die beiden Herbizide in einem Arbeitsgang ausgebracht werden könnten.     

The metabolism of benodanil in the rat

The metabolism of benodanil (2-iodobenzanilide) was studied in rats following an oral dose of 150 mg benodanil kg^?1 body weight. The major 24-h urinary metabolite was found to be the 4′-hydroxy derivative, both free (≈ 5%) and as the glucuronide (≈ 4%) and sulphate (≈ 4%) conjugates. Over a 6-day period, about 16% of the administered dose was excreted in the urine and about 80% in the faeces. After dosing with [¹⁴C]- benodanil, blood radioactivity levels were highest 30 min after dosing, with small broader peaks at 4 and 7 h, while biliary activity levels rose slowly to a maximum about 10–12 h after the dose, some 16% being excreted in 24 h as the glucuronide conjugate of the 4′-hydroxy derivative.     

The metabolism of chlorotoluron in the rat

The metabolic fate of ¹⁴C-labeled chlorotoluron, i.e., 1-(3-chloro-4-methyl[⁴C]-phenyl)-3,3-dimethyl urea, was followed in rats. After a single oral dose the radioactivity was preferably excreted with the urine. Nine of the eleven urinary metabolites isolated, were identified by spectroscopic and derivatization techniques, whereas the structure of the remaining two metabolites was only partially elucidated. N-Demethylation and stepwise oxidation of the ring methyl group to hydroxymethyl and carboxyl derivatives were found as the major metabolic mechanisms. Both mechanisms proceeded simultaneously so that the isolated metabolites showed all combinations of N-demethylation and ring methyl group oxidation in their structures. One of these metabolites was an N-formyl derivative, being probably an intermediate product of demethylation. In the urine of rats fed doses of [¹⁴C]chlorotoluron higher than 50 mg/kg three additional metabolites with different degrees of N-dealkylation were found, the ring methyl group of which was transformed to a methylthio methyl group. The metabolites identified in the faeces were of the same type as those found in the urine. Based on the structures of the metabolites elucidated, a metabolic pathway of chlorotoluron in the rat is presented.     

Acifluorfen metabolism in soybean: Diphenylether bond cleavage and the formation of homoglutathione, cysteine, and glucose conjugates

Metabolism of the substituted diphenylether herbicide, acifluorfen [sodium 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate], was studied in excised leaf tissues of soybean [Glycine max (L.) Merr. ‘Evans’]. Studies with [chlorophenyl-¹⁴C]- and [nitrophenyl-¹⁴C]acifluorfen showed that the diphenylether bond was rapidly cleaved. From 85 to 95% of the absorbed [¹⁴C]acifluorfen was metabolized in less than 24 hr. Major polar metabolites were isolated and purified by solvent partitioning, adsorption, thin layer, and high-performance liquid chromatography. The major [chlorophenyl-¹⁴C]-labeled metabolite was identified as a malonyl-β- -glucoside (I) of 2-chloro-4-trifluoromethylphenol. Major [nitrophenyl-¹⁴C]-labeled metabolites were identified as a homoglutathione conjugate [S-(3-carboxy-4-nitrophenyl) γ-glutamyl-cysteinyl-β-alanine] (II), and a cysteine conjugate [S-(3-carboxy-4-nitrophenyl)cysteine] (III).     

The metabolism of the carbamate insecticide bendiocarb in the rat and in man

The metabolism of the carbamate insecticide bendiocarb (2,2-dimethylbenzo-1, 3-dioxol-4-yl methylcarbamate) has been investigated in male and female rats and in a male human volunteer using radiolabelled material. The compound was rapidly and extensively absorbed and completely metabolised following oral administration. In man, absorption was complete, >99% of the dose being excreted in the urine within 22 h. In the rat, > 86% of the radiolabel was excreted in the urine within the first 24 h. Faecal excretion from the rat was minor (3–8% of dose) and a small amount of the compound (1–3%) was metabolised and excreted as [¹⁴C]carbon dioxide. The major metabolic pathway in both species involved cleavage of the carbamate ester group to yield the phenol,2,2-dimethylbenzo-1, 3-dioxol-4-ol (I). This metabolite, occurring as sulphate and glucuronide conjugates, accounted for more than 95% of the dose excreted by the human volunteer. In man, small amounts of conjugates of 2, 2-dimethylbenzo-1, 3-dioxol-4-yl N-(hydroxymethyl)carbamate (II) were also found in early samples. In the rat, the metabolism was more complex with the formation of small amounts of conjugates of II and several minor metabolites, thought to be ring-hydroxylated derivatives of bendiocarb and I.     

糠菌唑在大鼠、小鼠、兔、狗和人肝微粒体中的立体选择性代谢

采用高效液相色谱-串联质谱 (HPLC-MS/MS) 手性色谱柱法定量分析肝微粒体中的糠菌唑,通过密度泛函理论计算光谱与振动圆二色光谱 (VCD) 和红外光谱 (IR) 比对,确定了糠菌唑4种对映体的绝对构型;以大鼠、小鼠、兔、狗和人肝微粒体为模型,研究了糠菌唑的立体选择性降解行为。结果表明:在供试肝微粒体中,4种异构体的降解均遵循一级反应动力学方程,且在人和小鼠肝微粒体中的代谢速率相对较慢。(2S, 4R)-和 (2R, 4S)-糠菌唑在5种供试肝微粒体中的立体选择性趋势一致,而 (2R, 4R)- 和 (2S, 4S)-糠菌唑只在兔肝微粒体中的降解有显著的立体选择性差异,在小鼠肝微粒体中几乎没有立体选择性。酶促反应动力学结果也证实了糠菌唑代谢的立体选择性,并显示 (2R, 4R)- 和 (2S, 4S)-糠菌唑在供试肝微粒体中的酶促反应趋势存在种属差异。     

Studies of the metabolism of 3-phenoxybenzoic acid in plants

The metabolism of ¹⁴C-labeled 3-phenoxybenzoic acid, PBA, has been studied in cotton, vine, broad bean, soya bean, pea, lettuce, and tomato, using abscised leaves. PBA was converted into a range of polar products by esterification with glucose (in cotton and other species) and with glucosylarabinose and glucosylxylose (especially in vine leaves). Uptake of the glucose ester itself by cotton leaves also led to conversion into a more polar conjugate, probably the glucosylarabinose ester, which was not detectable following uptake of PBA. When PBA was applied to the surface of intact cotton leaves, it was slowly converted into products similar to those above.     

螺虫乙酯在染毒雄性大鼠体内的分布与代谢

建立了采用超高效液相色谱-串联质谱仪(UPLC-MS/MS)检测不同动物样品中螺虫乙酯及其主要代谢物残留量的方法,并研究了螺虫乙酯在大鼠体内的吸收与代谢。样品中螺虫乙酯及其主要代谢物经甲醇提取及C18固相萃取(SPE)柱净化后,用UPLC-MS/MS检测。结果显示,所建立方法快速、灵敏,每个样品上机检测仅需3 min,方法的最低检出浓度(LOQ)为0.005 mg/kg。对按照每千克体重每日250 mg剂量染毒28 d后的大鼠体内螺虫乙酯残留量的检测结果表明:螺 虫乙酯在睾丸、肝脏、肺、肾、心脏、血浆等器官和组织中的残留量较低,平均在0.012~0.025 mg/kg 之间,且分布差异不显著,而脂肪和肌肉中螺虫乙酯的残留量显著低于睾丸和肝脏中的残留量(P P 肾>血浆>肺>心脏>睾丸>脂肪>肌肉。     

Perfusion analysis of periportal and centrilobular metabolism of paraoxon in the rat liver

Paraoxon infused into the rat liver during perfusion in situ with Waymouth's medium underwent chromatographic translobular migration with an apparent hepatic transit time of 3 min. Intralobular heterogeneity of paraoxon metabolism was examined by analyzing metabolites produced under conditions minimizing the chromatographic translobular migration of paraoxon. Periportal and centrilobular activities were estimated following forward and retrograde infusion of paraoxon, respectively. Centrilobular hepatocytes exhibited nearly twice the metabolic rate of the periportal cells. Pretreatment of the rat with DDE resulted in about a threefold increase in the ratio of oxidative deethylation to hydrolytic dearylation in the centrilobular region. The differentials observed by these analyses were less pronounced than expected from enzyme analyses in vitro, possibly reflecting secondary metabolism or intracellular heterogeneity of metabolic activities.     

Comparative metabolism and disposition of [14C-benzyl] cypermethrin in quail,rat and mouse

The excretion and metabolism of cis + trans-[¹⁴C-benzyl] cypermethrin has been compared in quail, rat and mouse. Radioactivity was rapidly eliminated by quail dosed orally with [¹⁴C]cypermethrin (2 mg kg^?1), as was the case in the rat and the mouse. When the birds were dosed intraperitoneally (IP) with the ¹⁴C-labelled pyrethroid, radioactivity was excreted more slowly than after oral dosing, and almost 20% of the IP dose of ¹⁴C remained in the tissues after 7 days. Both mammalian species excreted [¹⁴C]cypermethrin more rapidly than did the avian species after IP administration, and less than 6% of the dose remained in their tissues after several days. The biotransformation of the pyrethroid was more complex in the avian species (34 metabolites) than in the two mammals (some 10 metabolites in each species). In quail the predominant reactions were ester bond cleavage of cypermethrin together with either aromatic hydroxylation or amino acid conjugation of the 3-phenoxybenzyl moiety. The hydroxylated derivatives were eliminated mainly as sulphates. 3-Phenoxybenzoic acid was conjugated with a variety of amino acids including glycine, taurine, glutamic acid, serine, α-N-acetylornithine and the dipeptide glycylualine. The last two conjugations are unique to avian species. The major metabolite of cypermethrin in the rat was the sulphate conjugate of 3-(¹⁴-hydroxyphenoxy)benzoic acid, whereas in the mouse the major products were 3-phenoxybenzoic acid and its taurine conjugate. Thus, in the mammalian species where hydroxylation was maximal, amino acid conjugation was a minor metabolic route und vice versa. However, in the quail, aromatic hydroxylation and amino acid conjugation of the 3-phenoxybenzyl moiety of cypermethrin were both major reactions. The influence of the rates and sites of metabolism, and of the enzymology of amino acid conjugation, in determining this species difference are discussed. The rapid metabolism of cypermethrin to a variety of polar conjugates that are readily excreted, together with the low brain sensitivity of birds compared with mammals to its neurotoxic effects, explains the low acute toxicity of this pyrethoid to avian species.     

Reductive metabolism of heptachlor,parathion, 4,4′-dichlorobenzophenone,and carbophenothion by rat liver systems

An attempt was made to survey systems which carry out reduction of four pesticidal chemicals, heptachlor, parathion, 4,4-dichlorobenzophenone, and carbophenothion sulfoxide, in rat liver microsomes and in the supernatant in vitro. On the basis of the stimulatory effects of nicotinamide cofactors (NADPH and NADH), a flavin cofactor (FAD), localization of the systems, and their sensitivities to heat-inactivation treatment, four different reductive systems were recognized. They are (a) the mixed-function oxidase-coupled reductive systems, (b) an independent NADH-stimulated (instead of NADPH as above) microsomal system for parathion reduction, (c) FAD-stimulated system for reduction of carbophenothion sulfoxide and parathion, present specifically in the supernatant, and (d) a heat stable, nonenzymatic reduction system in the microsomes operated by flavoproteins and a flavin cofactor.     

The metabolism of [14C] cymoxanil in the rat

A rat, given a single oral dose of [¹⁴C] cymoxanil, 1-(2-cyano-2-methoxyimino-[2-¹⁴C]-acetyl)-3-ethylurea, eliminated 91% of the radioactivity within 72 h. The urine contained 71%, the faeces 11%, and the expired air about 7% of the radiolabel; no ¹⁴C residue was found in the internal organs. Greater than 70% of the radioactivity in the urine was identified. The major metabolite was characterised as glycine, both free and conjugated, as hippuric acid and phenylaceturic acid [N-(phenylacetyl)-glycine], and probably in the form of polypeptides of low molecular weight. The other metabolites identified included 2-cyano-2-methoxyiminoacetic acid, 2-cyano-2-hydroxyiminoacetic acid and 1-ethylimidazolidine-2, 4, 5-trione. The minor metabolites included succinic acid and 2-oxoglutaric acid which indicated reincorporation of metabolic ¹⁴C. Cymoxanil, as such, was not detected in the urine.     

Effect of liver enzyme induction on paraoxon metabolism in the rat

Orally administered [1-¹⁴C]ethyl paraoxon, O,O-diethyl-O-p-nitrophenyl phosphate, is readily absorbed from the gastrointestinal tract of male albino rats. Radioactivity is essentially eliminated in 72 hr by excretion into urine and feces and by expiration as ¹⁴CO₂. Compounds with radioactivity in the urine are tentatively identified as diethyl phosphoric acid, desethyl paraoxon, ethanol, metabolites conjugated with amino acids, and paraoxon; the first compound is the predominant radioactive metabolite. Intraperitoneally injected phenobarbital, DDT, dieldrin, and endrin are inducers of microsomal enzymes that degrade paraoxon. The aryl phosphate-cleaving activity in vitro is not dependent on the addition of NADPH. O-Dealkylation of paraoxon is catalyzed by microsomal enzymes that require NADPH and oxygen and are inhibited by carbon monoxide. Microsomal enzymes from rats pretreated with enzyme inducers give an increased rate of O-dealkylation of paraoxon. Reduced glutathione has little or no effect on paraoxon degradation by either microsomal or soluble enzymes. Actinomycin D inhibits O-dealkylation of paraoxon in vivo, as indicated by reduction of ¹⁴CO₂ formation, and in vitro, as indicated by decreased activity of microsomal O-dealkylase. The role of microsomal mixed-function oxidases and NADPH-dependent O-dealkylase in the metabolism of organophosphorus insecticides is discussed.     

Enantioselective metabolism and cytotoxicity of the chiral herbicide ethofumesate in rat and chicken hepatocytes

We investigated the metabolic kinetics and toxicity of ethofumesate (ETO) in rat and chicken hepatocytes using a chiral high-performance liquid chromatographic (HPLC) method. The metabolic of ETO in rat hepatocytes was enantioselective, whereas it was not in chicken hepatocytes. The T_1/2 of (−)-ETO was about two times longer than that of (+)-ETO after the rat hepatocytes had been incubated with 20 μM rac-ETO. There was no chiral conversion or transformation during their incubation with the hepatocytes. Toxicity differences were observed between the two enantiomers of ETO, reflected in their EC₅₀ values in rat and chicken hepatocytes. The stereoselective cytotoxicity of the two enantiomers was opposite in rat and chicken hepatocytes. We have developed a method of studying the toxicokinetics and cytotoxicity of chiral agrochemicals in hepatocytes isolated from mammals (rats) and chicken. The data presented here allow a more thorough understanding of this pesticide and should be useful in its full environmental assessment.     

Metabolic aspects of the toxicology of diazinon. I. Hepatic metabolism in the sheep,cow, pig,guinea-pig,rat, turkey,chicken and duck

The phosphorothionate insecticide diazinon was incubated with liver microsomes from the sheep, cow, pig, guinea-pig, rat, turkey, chicken and duck. Metabolism by liver slices of most of these species was also examined. Hydroxydiazinon, isohydroxydiazinon, dehydrodiazinon, their oxons and diazoxon were identified and determined quantitatively or semi-quantitatively. An eighth metabolite was tentatively identified as the 6-aldehyde analogue of diazinon. Yields and rates of production of these metabolites varied greatly between species. Production of oxons was not generally correlated with susceptibility to diazinon poisoning, although it was lowest in the least susceptible animal, the sheep. The degradation of oxons by liver slices was too slow to explain the low toxicity of diazinon to the mammals. The relative importance of hepatic and extrahepatic metabolism in determining toxicity to vertebrates is discussed.