The aquatic toxicity of "simple" organic compounds has been recognized as being closely related to their lipophilicity (hydrophobicity). The environmental behaviors of pesticides, such as accumulation in soil, contamination of aquasphere, residue levels in crops, and bioaccumulation through food chains as well as nondietary routes, are dependent on their distribution properties among various environmental phases. These distribution features are modeled by phase-distribution equilibrium constants such as soil absorption coefficient, water solubility, and bio-concentration factors in biota, including crops. This chapter reviews the measurement and estimation procedures of the log P for a wide range of organic compounds and the significance of the log P value in elucidating and predicting the environmental behavior of pesticides in terms of the quantitative structure–activity relationship (QSAR). The most frequently used hydrophobicity parameter is the log P [or log k(o/w)], where P [or k(o/w)] is the 1-octanol/water partition coefficient. Thus, the environmental toxicology of pesticides covering distribution patterns, persistence, and toxicity could be quantitatively analyzable in terms of physicochemical molecular descriptors including hydrophobic, electronic, steric, and others with the use of regression analyses, in which the log P value is regarded as playing a central role.

A sulfoxide, isoprothiolane sulfoxide, has recently been found to be easily and exclusively reduced to isoprothiolane by a living rice plant.1} This is the first evidence for sulfoxide reduction by plants. Since isoprothiolane sulfoxide is an oxidative metabolite of isoprothiolane,2) an interconversion between a thioether and the corresponding sulfoxide may occur in rice plants, in which the balance of the interconversion inclines to the thioether. More recently, the reduction of another sulfoxide, methionine sulfoxide, by various plants has also been studied in our laboratory and will be discussed here.

The mode of selective toxicity of fenpyroximate (tert-butyl (E)-alpha-(1,3-dimethyl-5-phenoxypyrazol-4-ylmethyleneamino-oxy)-p-toluate), a potent acaricide, was studied with respect to its detoxification metabolism. Among its metabolites examined, only ester hydrolyzed metabolites completely lost the inhibitory activity toward NADH-ubiquinone oxidoreductase, which suggested that ester hydrolysis was the hey step in detoxification. After a single oral administration of fenpyroximate to rats, two labile intermediates (metabolites A and B) as well as ester hydrolyzed metabolites were found in the liver and plasma as the major metabolites. These intermediates were also observed in an vitro metabolism system employing rat liver S-9 (9000g supernatant) fraction under the presence of diisopropyl fluorophosphate, a carboxyesterase inhibitor. Metabolites A and B were isolated and identified as 1-hydroxymethyl-1-methylethyl (E)-alpha-(1,3-dimethyl-5-phenoxypyrazol-4-ylmethyleneamino-oxy)-p-toluate and 2-hydroxy-2-methylpropyl (E)-alpha-(1,3-dimethyl-5-phenoxypyrazol-4-ylmethyleneamino-oxy)-p-toluate, respectively. Under slightly basic conditions or in rat plasma, metabolite A was stoichiometrically and nonenzymatically converted to metabolite B most likely via intramolecular transestrification. The rate of in vitro metabolite A production was approximately 10 times greater than that of direct carboxyesterase hydrolysis of fenpyroximate; metabolite B was hydrolyzed approximately 100 times faster than fenpyroximate by carboxyesterase. Therefore, it is presumed that fenpyroximate is hydrolyzed principally via hydroxylation of fenpyroximate to metabolite A followed by transesterification to metabolite B in the rat. Hydroxylation of fenpyroximate to metabolite A was observed not only in mt liver, but also in mouse, rabbit, crab-eating monkey, carp, quail liver, and Spodoptera litula mid gut. Neither tertiary butyl ester hydrolysis nor metabolite A formation was detected in Tetranychus urticae Koch (two spotted spider mites), a fenpyroximate-sensitive organism in vitro and in vitro. Consequently, selectivity of fenpyroximate between spider mitts and non-target organisms, especially mammals, would be attributable to the species-specific detoxification, ester hydrolysis via microsomal hydroxylation followed by intramolecular transesterification. (C) 2000 Academic Press.

An analytical method for determining residues of buprofezin (2-tert-butylimino-3-isopropyl-5-phenylperhydro-1,3,5-thiadiazin-4-one) and its p-hydroxy metabolite (p-hydroxybuprofezin, one of its major metabolites in plants) in crops such as rice, citrus, and tomato was investigated. On the basis of the basicity of these compounds, a liquid-liquid partition, rather than column chromatography, was used for cleanup. Samples were extracted with acetone or methanol, and the concentrated extracts were partitioned between n-hexane and 1N HCl. After the aqueous layer was neutralized with 10N NaOH, the compounds were extracted with n-hexane,and the extract was analyzed with a gas-liquid chromatograph (GLC) equipped with an alkali flame ionization detector (AFID). p-Hydroxy-buprofezin was detected after acetylation with acetic anhydride-pyridine because its peak was broad and showed tailing on GLC. The limits of detection for buprofezin and p-hydroxybuprofezin were 0.005 ppm in hulled rice, citrus flesh, and tomato and 0.01 ppm in rice straw and citrus peel. Recoveries of both compounds fortified at 0.1 or 0.2 ppm were 75-97%.

Degradation of [pyrazole-3-C-14]- or [benzyl ring-C-14(U)]fenpyroximate (tert-butyl (E)-alpha-[1,3-dimethyl-5-phenoxypyrazol-4-ylmethyleneamino-oxy]-p-toluate) was studied in Ehime (diluvial) and Kanagawa (volcanic ash) soils under upland laboratory conditions. Soils (25 g) fortified with C-14-fenpyroximate (1.30-2.12 ppm) were incubated at 25-degrees-C for 112 days in the dark, The compound degraded with half-lives of 34.3-49.7 days in the Ehime soil and of 26.3-35.6 days in the Kanagawa soil. In the soil extracts, twelve degradation products were identified by TLC-co-chromatography with authentic compounds. Major degradation products were (E)-4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)-methyleneaminooxymethyl]benzoic acid (5), 1,3-dimethyl-5-phenoxypyrazole-4-carboxylic acid (12) and 1,3-dimethyl-5-phenoxypyrazole-4-carbonitrile (9). In both soils, C-14-carbon dioxide liberated from [pyrazole-C-14]fenpyroximate during the 112 days accounted for 16.9-17.1% of the applied radioactivity, and that from [benzyl-C-14]fenpyroximate for 51.2-64.6%. Fenpyroximate degradation and CO2 evolution were negligible in sterilized soils during the incubation. It was assumed that fenpyroximate degraded through hydrolysis of tert-butyl ester, isomerization or cleavage of the oxime ether structure, N-demethylation, oxidation of the methyl group at the 3-position on the pyrazole ring and hydroxylation of the phenoxy ring, and that it finally mineralized to CO2 and/or bound to soil organic matter.

Metabolism of fenpyroximate, tert-butyl (E)-alpha-(1,3-dimethyl-5-phenoxypyrazol-4-yl-methyleneaminooxy)-p-toluate in rats was studied. After a single oral administration of [pyrazole-3-C-14], [phenyl-C-14(U)] or [benzene ring-C-14(U)]fenpyroximate, the radiocarbon level in the blood increased to reach the maximum level of 0.18, 0.16 or 0.18 mug fenpyroximate eq./ml at 12, 12 or 9 hr, respectively, and then decreased at a half-life of 11.3, 10.6 or 9 hr, respectively. The radiocarbons in C-14-fenpyroximate were rapidly and almost completely excreted into the urine and feces within 72 hr. The excretion rates of radiocarbon into the urine and feces were 26.2 and 65.5% for [pyrazole-3-C-14], 26.1 and 63.9% for [phenyl-C-14(U)] and 6.4 and 86.90% for [benzene ring-C-14(U)]fenpyroximate, respectively. Urinary metabolites identified were 1, 3-dimethyl-5-phenoxypyrazole-4-carboxylic acid, 4-cyano-1-methyl-5-phenoxypyrazole-3-carboxylic acid and terephthalic acid. Major metabolites in the feces were (E)-4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)methyleneaminooxymethyl]benzoic acid, (E)-2-[4-[(1,3-dimethyl-5-phenoxypyrazol-4-yl)methyleneaminooxymethyl]benzoyloxy]-2-methylpropionic acid, (E)-2-[4-[[1,3-dimethyl-5-(4-hydroxy)phenoxypyrazol-4-yl]methylene-aminooxymethyl]benzoyloxy]-2-methylpropionic acid, (E)-2-[4-[(1-hydroxymethyl-3-methyl-5-phenoxypyrazol-4-yl)methyleneaminooxymethyl]benzoyloxy]-2-methylpropionic acid and 4-hydroxymethylbenzoic acid. Fenpyroximate seemed to be metabolized via oxidation of the t-butyl group and methyl group at 3-position in the pyrazole ring, p-hydroxylation in the phenoxy moiety, N-demethylation, hydrolysis of the t-butyl ester, cleavage of the oxime ether bond and/or E/Z isomerization.

Journal Article Rapid Hydrolysis Pathway for a Tertiary Alcohol Ester through Intramolecular Transesterification in Rats Get access Kazuhiko Motoba, Kazuhiko Motoba Institute for Life Science Research, NIHON NOHYAKU Co., Ltd., 4–31 Hondacho, Kawachinagano, Osaka 586, Japan Search for other works by this author on: Oxford Academic Google Scholar Hideo Nishizawa, Hideo Nishizawa Institute for Life Science Research, NIHON NOHYAKU Co., Ltd., 4–31 Hondacho, Kawachinagano, Osaka 586, Japan Search for other works by this author on: Oxford Academic Google Scholar Takashi Suzuki, Takashi Suzuki Institute for Life Science Research, NIHON NOHYAKU Co., Ltd., 4–31 Hondacho, Kawachinagano, Osaka 586, Japan Search for other works by this author on: Oxford Academic Google Scholar Hiroshi Hamaguchi, Hiroshi Hamaguchi Institute for Life Science Research, NIHON NOHYAKU Co., Ltd., 4–31 Hondacho, Kawachinagano, Osaka 586, JapanChemical Research Center, NIHON NOHYAKU Co., Ltd., 5–1–34 Tsukuda, Nishiyodogawa, Osaka 555, Japan Search for other works by this author on: Oxford Academic Google Scholar Matazaemon Uchida Matazaemon Uchida Institute for Life Science Research, NIHON NOHYAKU Co., Ltd., 4–31 Hondacho, Kawachinagano, Osaka 586, Japan Search for other works by this author on: Oxford Academic Google Scholar Bioscience, Biotechnology, and Biochemistry, Volume 56, Issue 2, 1 January 1992, Pages 366–367, https://doi.org/10.1271/bbb.56.366 Published: 01 January 1992 Article history Received: 20 September 1991 Published: 01 January 1992

To clarify the mode of antifungal action of NND-318, a new imidazole antimycotic, the effect of the agent on ergosterol synthesis in Trichophyton mentagrophytes and Candida albicans was examined, and compared to that of bifonazole.NND-318 was found to interfere with ergosterol biosynthesis by inhibition of sterol C-14 demethylation. In terms of drug concentrations exerting 50% inhibition of ergosterol biosynthesis, NND-318 was ≥25 times stronger than bifonazole.

The toxicities to Oryzias latipes, Daphnia pulex, and Chlorella vulgaris of nonspecific toxicants (alkanols, substituted benzenes, and alkyl toluates) were well collineated with the logarithm of the octanol/water partition coefficient, log K(ow). However, specific toxicants such as 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), lindane, diflubenzuron, rotenone, buprofezin, dieldrin, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), and fenvalerate exhibited excess toxicities dependent on the test organism species. The species-specific excess toxicities were much higher than those expected from log K(ow) and seemed to appear only when the test organisms possessed the specific sites for the toxicants. However, the toxicities of n-butyl- and n-propyl-p-toluates to Oryzias latipes were slightly lower than those predicted from log K(ow). The toxicity alleviation corresponded well to the ester biodegradability measured in the fish toxicity assay system. Thus simple quantitative structure-activity relationships (QSARs), using solely log K(ow) with an appropriate set of compounds and bioassay systems, are useful not only for predicting the environmental toxicity of nonspecific toxicants and specific toxicants, including their mechanism of action, but also for assessment of their biodegradability.

新しい抗真菌剤NND-318のin vitro抗真菌活性を既存のイミダゾール系薬剤と比較検討した.NND-318の抗真菌スペクトルは広範囲にわたり,皮膚糸状菌,酵母状真菌,黒色真菌,二形性真菌,Aspergillus属およびPenicillium属の各種病原性真菌に対して活性を示した.なかでも皮膚糸状菌を含む糸状菌および二形性真菌に対する抗真菌活性は,clotrimazoleのそれに比し1～64倍以上強いものであった.NND-318の活性は,clotrimazoleおよびbifonazoleと同様に,接種菌量の増大および血清添加により低下したが,培地の種類および培地のpHの変化に対してはNND-318の活性は比較的影響されなかった.また対照薬剤と同様に尿素との併用によりその活性は増強された.

The mode of action of fenpyroximate in Tetranychus urticae Koch (two-spotted spider mite) was studied biochemically and morphologically. Biochemical assays showed that an adult female T. urticae contained 88.96 ± 10.32 pmol ATP, which rapidly decreased to 74.8, 31.2, and 2.9%, 60 min after spraying with 0.05, 0.5, and 5 μg/ml fenpyroximate, respectively. The mortalities at that time were 2, 18, and 46%, respectively. In vitro experiments using rat liver mitochondria showed that 10 μ M fenpyroximate inhibited electron transport when NADH or NADH-linked substrates were used as the electron donors but not when succinate was used as the substrate. Therefore, the site of inhibition on the electron transport chain was considered to be the NADH-coenzyme Q (Co Q) reductase. Mitochondrial NADH-Co Q reductase of T. urticae was also inhibited by fenpyroximate, and the I 50 value was estimated to be 0.08 μ M . Transmission electron microscopy observations of T. urticae sprayed with 0.5 μg/ml fenpyroximate showed that the compound caused morphological changes in mitochondria in peripheral nerve cells such as swelling, irregular cristae arrangement, and lower matrix electron density. Similar morphological changes in mitochondria were also obvious in the ovaries and epidermal cells, but not in muscular cells or central nervous mass cells. These results indicate that the inhibition of mitochondrial NADH-Co Q reductase by fenpyroximate seems to induce a decrease in ATP contents and morphological changes in mitochondria. Ultimately, this would contribute to the acaricidal and knockdown activities against T. urticae by this compound.

NND-318前塗布による感染予防効果をpolyethylene glycol 300 (PEG 300)溶液および臨床試験用クリーム製剤を用いてclotrimazoleおよびbifonazoleのPEG 300溶液,ならびに市販クリーム製剤と比較した.各薬剤塗布1-4日後モルモット背部皮膚にTrichophyton mentagrophytesを接種し,薬剤による感染予防効果の持続性を感染成立数および感染部位の菌陽性率を指標に検討した.NND-318の1%溶液0.1mlを菌接種の1,2,3および4日前に1回塗布しておいた群では,感染成立数は12例中それぞれ0,1,0および2例,菌陽性率はそれぞれ3,7,8および21%であり,いずれの指標においてもclotrimazoleあるいはbifonazoleの1%溶液を塗布した群と比較して有意に低い値であった.NND-318の0.5%および1%クリーム製剤を1-4日前に1回塗布した群でも菌接種までの日数に応じて,感染成立数は12例中それぞれ1-8例および0例,菌陽性率はそれぞれ26-59%および0-13%の値を示し,clotrimazoleあるいはbifonazoleの1%市販クリーム製剤を前塗布したいずれの群と比較しても有意に,又は低い傾向にあった.以上の成績から,NND-318はPEG 300溶液およびクリーム製剤ともに対照薬に勝る感染予防効果を示し,薬効を発揮するのに充分なNND-318が皮膚に貯留していることが示唆された.

Trichophyton mentagrophytesの形態および微細構造に及ぼすNND-318の影響を走査型電子顕微鏡および透過型電子顕微鏡を用いて観察した.段階的濃度の薬剤を含む培地にT.mentagrophytes分生子を接種し,27℃で60時間スライド培養した.薬剤無添加では菌糸はほぼ直線状に伸長していたが,NND-318 0.08～0.4ng/ml添加では菌糸の屈曲,過剰分岐,菌糸幅の不均一化および皺襞形成等の形態変化が認められた.菌糸細胞内では,細胞壁の肥厚および壁内の顆粒状構造物出現,ならびに細胞質内の脂肪滴の増加が薬剤濃度の上昇に伴い認められた.0.8～1.6ng/mlでは菌糸の皺襞は更に明瞭となり,伸長は著しく阻害されていた.4.0ng/ml以上の濃度では菌糸形成は認められず分生子の形態を留めていた.比較対照のために用いたbifonazoleもまたより高濃度域ではあるがNND-318と同質の形態異常を引き起こすことが観察された.以上の結果からNND-318は従来のイミダゾール剤よりも著しく低濃度でT.mentagrophytes分生子の発芽ならびに菌糸の伸長発育を阻害すること,および発育を阻止された菌糸細胞においては細胞質内への脂肪滴の蓄積,細胞壁の肥厚,細胞壁内の顆粒状構造物形成促進などの超微形態学的変化が引き起こされることが示された.