Enhanced hepatotoxicity of carbon tetrachloride, thioacetamide, and dimethylnitrosamine by pretreatment of rats with ethanol and some comparisons with potentiation by isopropanol.

Elevated plasma glutamic-pyruvic transaminase (GPT) activity induced by carbon tetrachloride (CCl₄), thioacetamide, or dimethylnitrosamine in male rats was increased by pretreatment with four doses (each 5 ml/kg) of ethanol orally 48, 42, 24, and 18 hr before the hepatotoxic agent. The potentiated hepatotoxicity of CCl₄ was confirmed by histologic evaluation. During the pretreatment, blood ethanol concentrations fluctuated between 0 and 300 mg/100 ml, but were less than 5 mg/100 ml when a hepatotoxic agent was injected ip. Pretreatment with ethanol did not affect the hepatic concentrations of CCl₄ or its metabolite, chloroform (CHCl₃), at 1 hr after administration of CCl₄. The CCl₄-induced diene conjugation tended to increase after ethanol pretreatment and was significantly potentiated by pretreatment with isopropanol or pyrazole and a single dose of ethanol. In rats pretreated with ethanol, covalent binding of ¹⁴CCl₄ to liver protein and lipid in vivo was significantly greater at 6 and 24 hr, but not during the first 3 hr, than in control rats. The in vitro binding of ¹⁴CCl₄, ¹⁴CHCl₃, and ¹⁴CBrCl₃ to hepatic microsomal protein was increased by ethanol pretreatment. Ethanol pretreatment also doubled the in vitro rate of demethylation of dimethyl-nitrosamine by liver microsomes, but did not affect the amount of microsomal protein and cytochrome P-450, NADPH c reductase activity nor the rate of N-demethylation of ethylmorphine. The similarities in microsomal effects of pretreatment with isopropanol and pretreatment with four doses of ethanol suggest that similar mechanisms are involved in their potentiation of CCl₄-induced hepatotoxicity. The potentiation by pretreatment with ethanol, but not with isopropanol, of the hepatotoxicity of thioacetamide and dimethylnitrosamine suggests that ethanol pretreatment also activates some additional mechanisms.     

Reduction by pretreatment with dibenamine of hepatotoxicity induced by carbon tetrachloride, thioacetamide or dimethylnitrosamine

Pretreatment with dibenamine (25 mg/kg sc 48 and 24 hr before the administration of a hepatotoxic agent) protected rats against the hepatotoxicity of CCl₄, thioacetamide, or dimethylnitrosamine, but not against allyl alcohol or bromobenzene. Protection was evident from reduced activity of plasma glutamic-pyruvic transaminase and reduced liver necrosis as demonstrated by histologic evaluations. In rats pretreated with dibenamine, LD50 values for CCl₄ and thioacetamide were elevated and liver triglycerides after CCl₄ and dimethylnitrosamine were reduced. Dibenamine protection against hepatotoxicity did not correlate with alpha-adrenergic receptor blockade. Similar pretreatment with 3 other alpha-adrenergic blocking agents, tolazoline, phenoxybenzamine, and EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), failed to protect rats against CCl₄-induced hepatotoxicity.     

Lipid peroxidation induced by some halomethanes as measured by in vivo pentane production in the rat.

Pentane production in vivo in rats was used successfully as an index to support the concept that lipid peroxidation is involved in the toxicity of some halomethanes. The time-response relationships showed that the rats had maximum pentane production by 15–30 min following ip administration of carbon tetrachloride (CCl₄), bromotrichloromethane (BrCCl₃), and chloroform (CHCl₃). BrCCl₃ and CCl₄ caused the production of the greatest amounts of pentane, CHCl₃ induced a smaller amount of pentane production, and dichloromethane (CH₂Cl₂) did not increase pentane production over that caused by injection of the mineral oil carrier. There was a good relationship (r = 0.987; p < 0.001) between the amount of pentane produced and the bond dissociation energies of BrCCl₃, CCl₄, and CHCl₃. This finding supports the concept that trichloromethyl radicals (·CCl₃) produced by homolytic cleavage of halomethanes induce lipid peroxidation. Conjugated dienes in liver, kidney, intestine, spleen, lung, and heart were measured following administration of CCl₄ and BrCCl₃. There was a good correlation (r = 0.96; p < 0.01) between pentane production in vivo and conjugated diene formation in the liver. The liver accounted for 85 and 94% of the total conjugated dienes measured after administration of CCl₄ and BrCCl₃, respectively. The amount of pentane produced during a 30-min period following injection of 1 mmol of CCl₄ corresponded to about 0.2% of the lipid peroxides, measured as conjugated dienes, in the liver following the same time period. These results suggest that liver is also the principal site of pentane production.     

Mixed carboxylic-carbonic acid anhydrides of acylamino acids and peptides as a convenient source of 2,4-dialkyl-5(4H)-oxazolones

Racemic 2-R¹-4-R²-5(4H)-oxazolones (R¹= CH₃, C₆H₅, C₆H₅ CH₂ OCONHCH₂; R²= aliphatic and C₆H₅CH₂) have been prepared in good yields by reaction of the parent N-acetyl-, N-benzoyl-, and N-benzyloxycarbonylglycyl-amino acids with methyl chloroformate in cold dichloromethane in the presence of N-methylmorpholine, followed by washing the mixtures with aqueous solutions and removal of the solvent. The products derived from optically active substrates contained enantiometric excesses of 83–98%. The method cannot be applied to the preparation of oxazolones from N-formylamino acids.     

Effect of exercise or smoking on the uptake,metabolism, and excretion of methylene chloride vapor

The finding that CH₂Cl₂ is metabolized in vivo to carbon monoxide (CO) prompted us to study the absorption, metabolism, and excretion of CH₂Cl₂ in humans and in experimental animals, and to extend such studies to include the effect of physical exercise and smoking. Controlled exposures to CH₂Cl₂ were carried out at 100 ppm for $\text{7}\text{1}\text{2}$ hr with exercising or smoking individuals. Exercise was performed on a treadmill at light, moderate, or heavy workloads. Cigarettes were smoked during and after exposure to CH₂Cl₂. The concentration of CH₂Cl₂ in the blood and the end tidal air, of CO in the end tidal air, and of carboxyhemoglobin in the blood were determined during and after the exposure. Physical exercise increased the absorption of CH₂Cl₂, the biotransformation of CH₂Cl₂ to CO, blood carboxyhemoglobin saturations and the pulmonary excretion of CO compared to those values obtained from sedentary exposures. It is noteworthy, however, that there was no further increase in blood carboxyhemoglobin saturations in individuals exercising at moderate to heavy workloads. This was apparently due to a marked increase in the pulmonary excretion of CO while performing heavy workloads. The combined effect of smoking and exposure to CH₂Cl₂ produced an additive increase in blood carboxyhemoglobin values. These findings show that smokers or physically active workers exposed to 100 ppm of CH₂Cl₂ vapor may have slightly higher blood carboxyhemoglobin saturations than do sedentary nonsmokers.     

Structure--toxicity relationships of 1-substituted-4-alkyl-2,6,7-trioxabicyclo[2.2.2.]octanes.

Many trioxabicyclooctanes [X(OCH₂)₃CY] at low doses administered ip produce tonic-clonic convulsions and death in mice. When X is P, OP, SP, HC, alkyl-C, and C₆H₅C, the optimal Y substituent is tC₄H₉ among alkyl groups examined. In ortho carboxylic acid esters, the optimal X substituent is either small (potency decreases in the order HC > CH₃C) or large (C₆H₅C > nC₄H₉ > nC₃H₇C) while intermediate-sized substituents (C₂H₅C and iC₃H₇C) reduce or negate the toxic properties. Limited literature data on the toxicity of silatranes [X(OCH₂CH₂)₃N] suggest that they may fit a similar pattern for the optimal X substituent (C₆H₅Si > HSi > alkylSi). These findings and particularly the discontinuous sizeactivity relationships of X indicate that the ortho carboxylic acid esters include compounds that may act at two different nerve receptors: one receptor accepts HC(OCH₂)₃CY and CH₃C(OCH₂)₃CY, which mimic P(OCH₂)₃CY, OP(OCH₂)₃CY, SP(OCH₂)₃CY, and possibly HSi(OCH₂CH₂)₃N; the other accepts nC₃H₇C(OCH₂)₃CY, nC₄H₉C(OCH₂)₃CY, and C₆H₅C(OCH₂)₃CY, which may mimic C₆H₅Si(OCH₂CH₂)₃N.     

抗肿瘤药米铂的一种新合成方法及结构表征

目的 合成抗肿瘤新药米铂。方法 以顺式- (1R,2R)-1, 2-环己二胺-二碘合铂(II)为起始原料,先将顺式- (1R,2R)-1, 2-环己二胺-二碘合铂(II)与硫酸银水解成含有硫酸根的水合物溶液,然后与八水氢氧化钡反应生成顺式- (1R,2R)-1,2-环己二胺-二羟基合铂(II)的水溶液,最后与正十四碳酸的正丁醇溶液反应合成米铂。采用元素分析、质谱、红外光谱、核磁共振氢谱和热分析对其结构进行表征。结果与结论 合成的化合物结构与标题化合物一致,收率约68%。该方法便于操作,收率高,可做进一步研究。     

Anticancer activities of some arylcarbamoylalkyltriphenylphosphonium chlorides

A series of novel arylcarbamoylalkyltriphenylphosphonium chlorides were synthesized. The newly synthesized compounds, [R-(p-C₆H₄)-NH-CO-R₁P^⊕(C₆H₄)₃]Cl^θ, R = H (2), CH₃ (4), NO₂ (6), R₁ = –CH₂− (b), CH₃CH< (a), –CH₂CH₂− (c), –CH₂CH₂CH₂ (d), the analogs of an anticancer drug, were characterized by infrared (IR), ¹H nuclear magnetic resonance (NMR), ¹³C-NMR, ³¹P-NMR, mass spectrometry (MS), thermogravimetry (TG), and conductivity measurements. The anticancer activities of the obtained compounds were measured by MTT. The preliminary results indicated that some compounds showed potent anticancer activities against HCT-8, Bel-7402, A549, and S180.     

Hepatotoxicity and lethality of halomethanes in Mongolian gerbils pretreated with chlordecone,phenobarbital or mirex

The hepatotoxic and lethal effects of CBrCl₃, CCl₄ and CHCl₃ were investigated in gerbils with or without prior exposure to dietary chlordecone (CD), phenobarbital (PB) and mirex (MX) at 10, 225 and 10 ppm, respectively, for 15 days. Gerbils were quite sensitive to these halomethanes (48 h LD₅₀: 20, 80 and 400 l/kg, respectively). CD, known to potentiate hepatotoxic and lethal effects of halomethanes in rats, failed to potentiate the toxic effects of any of these three halomethanes in gerbils. PB and MX were also ineffective. Since stimulation of early hepatocellular regeneration has been shown to be responsible for the recovery from the toxicity of a low dose of CCl₄, liver cell regeneration and tissue repair were studied in gerbils after CCl₄ administration. The objectives of these studies were to investigate the possible reasons for the high sensitivity of gerbils to halomethane toxicity and to investigate the mechanism for their refractoriness to CD-potentiated halomethane toxicity. A low and a high dose of CCl₄ (15 and 80 l/kg, i.p. respectively) were used to study the time-course of liver injury in gerbils pretreated with or without CD. The low dose of CCl₄ stimulated cellular regeneration as indicated by the increase of³H-thymidine (³H-T) incorporation in hepatic nuclear DNA. The cellular regeneration and tissue repair activities resulted in complete recovery from the limited liver injury in both CD-pretreated and control gerbils. In contrast to rats, however, the process of cell division in gerbils occurred much later, 2 days after CCl₄ administration. Evidence from histomorphometric studies was consistent with serum enzyme and³H-T incorporation data. Significant increase in hepatocyte mitosis did not occur until 42 h after CCl₄ administration. Hepatic injury assessed as hepatocellular necrosis and lipid accumulation was evident as early as 24 h after CCl₄ injection and was maximal at 42 and 72 h after CCl₄ in CD-pretreated and control gerbils, respectively. Administration of a high dose of CCl₄ alone significantly impeded tissue repair. More than 65% of the hepatocytes were necrotic in both CD-pretreated and control gerbils 24 h after the administration of a LD₅₀ dose of CCl₄.³H-T incorporation did not increase up to 48 h after CCl₄ in either group. These findings suggest that the absence of early stimulation of hepatocellular division and tissue repair might be responsible for the very high toxicity of a low dose of CCl₄ in gerbils. Since there is no early tissue proliferative response in gerbils after CCl₄ administration, CD+CCl₄ interactive ablation of liver proliferative response cannot occur, making gerbils refractory to CD-potentiation of CCl₄ toxicity.A preliminary report of these findings was presented at the 29th Annual Meeting of the Society of Toxicology at Miami, Florida. Toxicologist (1990) 10: 209Recipient of the 1988 Burroughs Wellcome Toxicology Scholar Award.     

A gram‐scale synthesis of [3,4‐13C2,1α,7‐2H2]cortisone

A gram‐scale synthesis of [3,4‐¹³C₂,1α,7‐²H₂]cortisone from prednisone was developed. The deuterium atom at the C‐1 position was introduced through a regioselective and stereoselective deuteration of the 1,2‐double bond of the 1,4‐diene‐3‐one using Wilkinson's catalyst. After the oxidative cleavage of the A‐ring, two carbon‐13 atoms were introduced via acetylation of an A‐ring enol lactone with [1,2‐¹³C₂]acetyl chloride. The steroidal A‐ring was then reconstructed to incorporate the carbon‐13 atoms into the C‐3 and C‐4 positions. The deuterium atom at C‐7 was introduced through a regioselective deuteration of the 6,7‐double bond of a 4,6‐diene‐3‐one intermediate using palladium on strontium carbonate. The M + 4 stable isotope labeled cortisone was thus prepared in ca. 4% overall yield. In addition, [3,4‐¹³C₂,1α,7‐²H₂]‐11‐dehydrocorticosterone, [3,4‐¹³C₂,1α,7‐²H₂]cortisol, and [3,4‐¹³C₂,1α,7‐²H₂]corticosterone were also prepared. Copyright © 2011 John Wiley & Sons, Ltd.     

Prevention of carbon tetrachloride-induced necrosis by inhibitors of drug metabolism--further studies on their mechanism of action

Liver necrosis caused by CCl₄ is known to be decreased by the administration of SKF 525-A (2-diethylaminoethyl 2,2-diphenylvalerate), Sch 5705 (ethyl 2-diethyl-aminoethyl-2-phenyl-2-ethyl malonate), Sch 5706 [ethyl N-(2-diethylaminoethyl) 2-phenyl-2-ethyl malonate], Sch 5712 (ethyl 2-diethylaminoethyl 2-ethyl-2-butyl malonate), CFT 1201 [2-diethylaminoethyl 2-phenyl (2-propene) 4-penten-1-oate], Lilly 18947 (2,4-dichloro-6-phenyl phenoxyethyl diethylamine) and DPEA (2,4-dichloro-6-phenyl phenoxyethylamine). Although these substances are known to inhibit cytochrome P-450 dependent drug-metabolizing enzymes in liver microsomes, they apparently do not evoke their protective effects by slowing the elimination of CCl₄. In fact, SKF 525-A, but none of the other inhibitors, partially prevents the impairing effects of CCl₄ on cytochrome P-450 in liver. Although SKF 525-A markedly decreased the liver necrosis and the rise in serum isocitrate dehydrogenase (ICD) caused by CCl₄, it only partially prevented the CCl₄-induced decrease in body temperature.     

Oxygen-17 n.m.r. of peptides

Peptide-¹⁷O chemical shifts of linear dipeptides with and without protecting groups in H₂O, CH₃OH, CH₂Cl₂, CHCl₃, CCl₄, CH₃CN and DMSO were between 256–350 ppm downfield from external water. Increasing solvent H-bond donating ability correlated with shifts to higher field. The ¹⁷O resonance of several cyclic dipeptides appeared at higher field relative to comparable linear dipeptides (303–317 p.p.m. vs. 327–337 p.p.m.). Separate signals were simultaneously observed by ¹³C and ¹⁷O n.m.r. for cis and trans N-tert.-butyl-formamide in binary mixtures with H₂O, (CH₃)₂CO, and CCl₄. The differences in the ¹⁷O nuclear screening of the amide isomers and most probably for cis and trans peptides were independent of contributions from H-bonding at the amide or peptide linkage, apparently reflecting differences between geometric isomers in electron distribution and through space effects. Peptide-¹⁷O of Gly-Ala, Gly-Leu and Gly-Glu in aqueous solution experienced upfield shifts of 6–12 p.p.m. and 12–16 p.p.m. upon deprotonation of the C-terminal COOH and of the N-terminal NH+₃ groups respectively. These observations were rationalized in terms of the attendant changes in substituent effects, especially on the ± electron donating ability of the N atom at the peptide linkage and increased partial negative charge on the peptide oxygen. Temperature studies of peptide-¹⁷O of Gly-Ala between pH 1.5–9.0 revealed a chemical shift coefficient of 0.08 p.p.m./K and similar behavior of T₁ and T₂ relaxation times. Ea for molecular rotation was 5 kcal/mol between 301–331·K. Rotational correlation times, _c, were within the range expected from the Stokes-Einstein relation.     

The crystal and molecular structure of bromhexine·HCl

The crystals of bromhexine-HCl, C₁₄H₂₁ N₂Br₂Cl, are orthorhombic, space group Pca2₁ with a=14.598(2)Å, b=12.461(3)Å, c=9.186(1)Å and Z=4. Intensity data for 967 reflections (Fobs>6σ(F)) were collected on a Rigaku-Denki automatic fourcircle diffractometer. The structure was solved by the Patterson and Fourier methods. Refinements were carried out to the final R value of 0.082. The cyclo-hexane ring has a normal chair form and the benzene ring is planar. There are three independent hydrogen bonds in the structure. One is an intermolecular hydrogen bond (N-H…Cl^?) and the others are intramolecular hydrogen bonds (N-H…Br, N⁺-H…Cl^?). Apart from the hydrogen bonding system the molecules are held together in the crystal by van der Waals force.     

Potentiation of brominated halomethane hepatotoxicity by chlordecone in the male rat

The potentiation of hepatotoxicity by CCl₄ and a series of brominated analogs by chlordecone (CD) and phenobarbital (PB) pretreatment was investigated, using individually nontoxic levels of the halomethanes and the potentiating agents. Hepatotoxicity was determined by biochemical, functional, and histopathological parameters. Male Sprague-Dawley rats were maintained on a diet of 0 or 10 ppm CD or 225 ppm PB for 15 days. On Day 15, the animals were challenged with an approximately equimolar ip dose (10 μl/kg) of CCl₄, CCl₃Br, CBr₄, or CHBr₃ in corn oil. Twenty-four hours later, biliary excretion of phenolphthalein glucuronide (PG) and bile flow were determined in intact cannulated animals over a 60-min period. While biliary excretion of PG was significantly decreased by CD-CCl₃Br and PB-CBr₄ combinations, the former combination was not accompanied by decreased bile flow. Of the four halomethanes tested, CD significantly elevated serum transaminase (SGPT, SGOT) and isocitrate dehydrogenase (ICD) activities only for the CCl₃Br combination, while phenobarbital treatment was without effect. Histopathological examination indicated that livers from the CD-CCl₃Br combination alone displayed extensive centrilobular necrosis. Based on these features of hepatotoxicity, CD resulted in readily observable potentiation of CCl₃Br hepatotoxicity. The PB-CCl₃Br combination did not result in potentiated CCl₃Br hepatotoxicity at the dose level utilized in this study. These results emphasize the extremely powerful nature of the CD-CCl₃Br interaction.     

滇产植物的皂素成分研究 Ⅰ.滇吉祥草的甾体成分(1)

从滇吉祥草(Reineckea yunnanensis W.W.Smith)中分得两个甾体皂甙元,其一为薯蓣皂甙元(diosgenin),另一皂甙元暂名为滇吉祥草皂甙元(yunnanogenin),熔点275—277℃,[α]_D^17°—64.1(CHCl₃,c=0.156),制成双乙酰化物,熔点181—182℃,双苯甲酰化物,熔点236—239℃,23-溴代双乙酰化物,熔点196—199℃。由上述数据及红外吸收光谱数据,推测为一正系饱和的双羟基皂甙元。     

中国乌头的研究——Ⅹ.关白附子中的新生物碱

从关白附子(Aconitum koreanum R.Raymund)中共分得六种生物碱。其中一种是已知生物碱,卽次乌头碱,另五种为新生物碱,暂称为关附甲素C₂₄H₃₁O₆N、乙素C₂₂H₂₉O₅N、丙素C₂₂H₃₃O₂N、丁素C₂₄H₃₅O₃N及戊素C₂₉H_(43)O₇N。关附甲素是关附乙素的一乙酸酮。关附甲素、乙素、丙素的示性式分别定为:C₁₉H₂₀(OH)₂(CH₃COO)₂(CH₃)(∶N·),C₁₉H₂₀(OH)₃(CH₃COO)(CH₃)(∶N·),C₁₉H₂₃(OH)₂(CH₃)(N—C₂H₅)。后二种生物碱因量少尚待研究。     

Novel heteroleptic complexes of titanium(IV) derived from 2-hydroxyacetophenone: synthesis, characterization, antibacterial and molecular docking studies

A few new and versatile complexes of titanium(IV) derived from 2-hydroxyacetophenone of the types {[(Ap)Ti(OPr ⁱ )_2?n (L₂) _n ] (2a, 2e and 2f)}, {[(Ap)Ti(L₁OR)(L₂)] (2b–2d, 2g–2i)} have been synthesized by the reaction of the precursor [(Ap)Ti(OPr ⁱ )₂] with different 2-heteroaryl methyl ketone oximes and alkoxyalkanols in various molar ratios in refluxing toluene yielded mono nuclear heteroleptic derivatives, {where, n = 1–2, HAp = 2-hydroxyacetophenone, Pr ⁱ  = isopropyl, L₁ = O–CH₂–CH₂?, R = CH₃, C₂H₅, C₄H₉ and HL₂=HONC(Me)py-2, HONC(Me)fu-2}. All these newly synthesized complexes were characterized by elemental analysis, mass, UV, FT-IR and NMR (¹H, ¹³C) spectral studies. The mass spectra of the newly synthesized molecules indicate their monomeric state. Spectral studies suggest the bonding between metal and ligands in a tetra coordinated fashion. Thermogravimetric analyses indicate the multistep decomposition of complexes resulting TiO₂ as the end product at 600 °C. Antibacterial activities of these complexes were also exercised. Complex 2e is equipotent to the standard drug against Pseudomonas aeruginosa and Escherichia coli. A keen molecular docking study revealed lesser docking scores of some of these complexes than that of the standard drug gentamicin.     

Channel‐forming,self‐assembling,bishelical amphiphilic peptides: design,synthesis and crystal structure of Py(Aibn)2, n = 2, 3, 4

Abstract: The design, synthesis, characterization and self‐assembling properties of a new class of amphiphilic peptides, constructed from a bifunctional polar core attached to totally hydrophobic arms, are presented. The first series of this class, represented by the general structure Py(Aib_n)₂ (Py = 2,6‐pyridine dicarbonyl unit; Aib = α, α′‐dimethyl glycine; n = 1–4), is prepared in a single step by the condensation of commercially available 2,6‐pyridine dicarbonyl dichloride with the methyl ester of homo oligoAib peptide (Aib_n‐OMe) in the presence of triethyl amine. ¹H NMR VT and ROESY studies indicated the presence of a common structural feature of 2‐fold symmetry and an NH…N hydrogen bond for all the members. Whereas the Aib3 segment in Py(Aib3)₂ showed only the onset of a 3₁₀‐helical structure, the presence of a well‐formed 3₁₀‐helix in both Aib4 arms of Py(Aib4)₂ was evident in the ¹H NMR of the bispeptide. X‐ray crystallographic studies have shown that in the solid state, whereas Py(Aib2)₂ molecules organize into a sheet‐like structure and Py(Aib3)₂ molecules form a double‐stranded string assembly, the tetra Aib bispeptide, Py(Aib4)₂, is organized to form a tetrameric assembly which in turn extends into a continuous channel‐like structure. The channel is totally hydrophobic in the interior and can selectively encapsulate lipophilic ester (CH₃COOR, R = C₂H₅, C₅H₁₁) molecules, as shown by the crystal structures of the encapsulating channel. The crystal structure parameters are: 1b , Py(Aib2)₂, C₂₅H₃₇N₅O₈, sp. gr. P2₁2₁2₁, a = 9.170(1) Å, b = 16.215(2) Å, c = 20.091(3) Å, R = 4.80; 1c , Py(Aib3)₂, C₃₃H₅₁N₇O₁₀·H₂O, sp. gr. P, a = 11.040(1) Å, b = 12.367(1) Å, c = 16.959(1) Å, α = 102.41°, β = 97.29°, γ = 110.83°, R₁ = 6.94; 1 da, Py(Aib4)₂?et ac, C₄₁H₆₅N₉O₁₂?1.5H₂O·C₄H₈O₂, sp. gr. P, a = 16.064(4) Å, b = 16.156 Å, c = 21.655(5) Å, α = 90.14(1)°, β = 101.38(2)°, γ = 97.07(1)°, Z = 4, R₁ = 9.03; 1db, Py(Aib4)₂?amylac,C₄₁H₆₅N₉O₁₂?H₂O ·C₇H₁₄O₂, P2₁/c, a = 16.890(1) Å, b = 17.523(1) Å, c = 20.411(1) Å, β = 98.18 °, Z = 4, R = 11.1 (with disorder).     

Effect of agents known to alter carbon tetrachloride hepatotoxicity and cytochrome P-450 levels on carbon tetrachloride-stimulated lipid peroxidation and ethane expiration in the intact rat

Administration of carbon tetrachloride (CCl₄) to rats led to an increase in expired ethane by 15 min. Prior treatment of rats with phenobarbital led to a significant increase in both CCl₄-stimulated ethane expiration and hepatic microsomal lipid diene conjugation, while prior treatment with 3-methylcholanthrene or CCl₄ led to a decrease in both parameters. Treatment with isopropanol increased CQ₄-stimulated ethane expiration, while neither ethanol nor diethyl maleate treatment altered the response to CCl₄. Cobaltous chloride treatment significantly decreased CCl₄-stimulated ethane expiration. A strong correlation was found between CCl₄-stimulated hepatic microsomal lipid diene conjugation and ethane expiration.     

Oxidative metabolism of propylthiouracil by peroxidases from rat bone marrow

1.Propylthiouracil (PTU) was degraded by myeloperoxidase (MPO) or eosinophil peroxidase (EPO), purified from rat bone marrow, in the presence of H₂O₂ and Cl^?. In the absence of either H₂O₂ or Cl^?, MPO and EPO do not degrade PTU. Optimum concentrations of KCl for MPO and EPO were 50 and 250 mM, respectively.

2.The characteristics of PTU degradation by MPO-H₂O₂-Cl^? were similar to those of the chlorinating activity of the peroxidase.

3.Hypochlorous acid as well as MPO-H₂O₂-Cl^? also degraded PTU. Metabolites of PTU degradation by MPO-H₂O₂-Cl^?, which were separated by C₁₈ reversed phase h.p.l.c., were the same as those produced by hypochlorous acid.

4.Of the metabolites of PTU formed by MPO-H₂O₂-Cl^?, one was identified as PTU sulphonic acid (6-propyl-4-hydroxypyrimidine-2-sulphonate) and another seemed to be propyluracil.