Ella C. Kimmel

Bioorganotin chemistry: Reactions of tributyltin derivatives with a cytochrome P-450 dependent monooxygenase enzyme system☆

Abstract The biological oxidation of several tributyltin derivatives, by a cytochrome P-450 dependent monooxygenase enzyme system with reduced nicotinamideadeninedinucleotidephosphate as the essential cofactor, produced carbon-hydroxylated compounds identified as α-, β-, γ- and δ-hydroxybutyldibutyltin derivatives. The hydroxylation pattern and the lack of oxidative cleavage of tin-carbon bonds strongly suggest a free radical rather than an oxenoid mechanism, while the predominance of β-carbon-hydroxylation further implies some role of the tin-carbon σ electrons in directing the site of hydroxylation.

Sulfoxidation of thiocarbamate herbicides and metabolism of thiocarbamate sulfoxides in living mice and liver enzyme systems

Abstract The microsome-NADPH system of mouse liver oxidizes each of benthiocarb, butylate, cycloate, EPTC, molinate, pebulate, and vernolate herbicide chemicals to the corresponding thiocarbamate sulfoxide which is then cleaved by the liver soluble-glutathione system. These sulfoxides are also detected as transient metabolites in the liver of mice injected with EPTC, molinate, pebulate, and vernolate but not with the other three thiocarbamates. Thiocarbamate sulfones are not detected as metabolites of the thiocarbamates. Studies in vivo and in vitro with [14C]EPTC and -pebulate or their corresponding sulfoxides and/or sulfones further indicate that sulfoxidation is the initial metabolic step in cleavage of the thiocarbamate ester group. Sulfoxidation appears to be a detoxification mechanism for thiocarbamate herbicides in mammals.

DNA adduct formation by alachlor metabolites

The extent of DNA adduct formation by alachlor [ArN(CH2OCH3)C(O)CH2Cl wherein Ar is 2,6-diethylphenyl] and its metabolites is used as a guide to deduce the causal agent(s) in the carcinogenicity of this major herbicide. [14C-phenyl]Alachlor is compared to its two metabolic cleavage products, [14C-phenyl]2-chloro-N-(2,6-diethylphenyl)acetamide (CDEPA) [ArNHC(O)CH2Cl] and [14C-phenyl]2,6-diethylaniline (DEA) (ArNH2), and to [14C-methoxy]alachlor in various in vitro and in vivo systems. Horseradish peroxidase and hydrogen peroxide activate DEA, but not CDEPA or alachlor, for formation of adducts with calf thymus DNA, which probably involves 2,6-diethylnitrosobenzene (ArNO) as an intermediate. Mouse liver microsomes and NADPH are both required to enhance the binding from each labeled preparation to calf thymus DNA; 4-fold higher labeling is observed from [14C-methoxy]- than from [14C-phenyl]alachlor. This 4-fold preferential DNA labeling from the 14C-methoxy compound is likewise found in the liver of mice treated intraperitoneally. Mouse liver protein and hemoglobin are also labeled, in vivo, with [14C-phenyl]alachlor, -CDEPA and -DEA, and, as with the DNA, the labeling of these proteins is 1.5- to 2-fold higher with [14C-methoxy]alachlor. Metabolic studies indicate that ArN(CH2OCH2OH)C(O)CH2Cl is an intermediate in forming CDEPA and presumably formaldehyde in the mouse liver microsomal mixed-function oxidase system and in yielding the O-glucuronide of ArN(CH2OH)C(O)CH2Cl in the urine of alachlor-treated mice. These findings point to the N-CH2OCH2OH metabolite or formaldehyde as a reactive intermediate in forming a DNA-adduct and as a candidate proximate carcinogen.

Bioorganotin chemistry: biological oxidation of tributyltin derivatives

Abstract The biological oxidation of several tributyltin derivatives by a rat liver microsomal mixed function oxygenase produces carbon hydroxylated compounds identified as α-, β-, γ- and σ-hydroxylbutyldibutyltin derivatives. The mechanistic implications and the possible role of the tin atom in these oxidations are discussed.

Action on mitochondria and toxicity of metabolites of tri-n-butyltin derivatives

Abstract Tri- n -butyltin derivatives are metabolized by a cytochrome P450-dependent rat liver microsomal monooxygenase system and by mice to yield carbon-hydroxylated metabolites, i.e. the α-, β-, γ- and δ-hydroxybutyl-dibutyltin derivatives, as well as the corresponding γ-ketone. The latter three metabolites are sufficiently stable at physiological pH for comparisons with tributyltin chloride with regard to their action on mitochondrial functions and intraperitoneal toxicity to mice. The δ-hydroxy compound differs most greatly from the other metabolites in potency for altering mitochondrial functions possibly because of its greater polarity or its lower propensity for intramolecular coordination of the introduced oxygen with the tin atom. The γ-hydroxy, δ-hydroxy and γ-keto compounds are less toxic to mice than tributyltin derivatives and do not increase the water content of the brain under conditions where triethyltin bromide does.

Peracid-mediated n-oxidation and rearrangement of dimethylphosphoramides: plausible model for oxidative bioactivation of the carcinogen hexamethylphosphoramide (HMPA)

Abstract Dimethylphosphoramides react with m -chloroperoxybenzoic acid (MCPBA) in anhydrous acetone to yield the previously unknown P -dimdethylamino-oxyphosphonous derivatives via N -oxidation and rearrangement. Further MCPBA oxidation yields formaldehyde and nitrosomethane, isolated as its trans -dimer. These reactions provide a possible biomimetic model for the metabolic activation of hexamethylphosphoramide as a mutagen and carcinogen.

3-Substituted 2-halopropenals: mutagenicity, detoxification and formation from 3-substituted 2,3-dihalopropanal promutagens

The mutagenicity of halopropenals for Salmonella typhimurium strain TA100 is as follows (revertants/nmole): 2-halopropenals [H2C = C(X)CHO], F = less than 0.6, Cl = 135, Br = 1140 and I = less than 2.4; 3-substituted-2-halopropenals [CH3CH = C(X)CHO], Cl = 68 and Br = 108; [C6H5CH = C(X)CHO], Cl = less than 1 and Br = 5; [ClCH = C(Cl)CHO], 91; [CH3(CH2)2CH = C(Br)CHO], less than 1; [(CH3)2C = C(Br)CHO], less than 0.5. Each of the active compounds is detoxified by the liver S9 fraction. Glutathione also detoxifies the 2-halopropenals and 2-halobutenals, more rapidly for the bromo than the chloro analogs. The mutagenic potency on metabolic activation of the herbicide diallate by microsomes or the S9 fraction is attributable to approximately 50% conversion to 2-chloropropenal when corrected for detoxification in these systems or with GSH. There is no correlation between mutagenicity and reactivity with the model thiol, 4-nitrobenzenethiol. The mutagenicity of 2,3-dichloro- and 2,3-dibromo-propanals and the corresponding dihalobutanals is accounted for by their rapid dehydrohalogenation to the corresponding 2-haloalkenals under physiological conditions. Chemicals that are metabolized to 2,3-dichloropropanal, 2,3-dichlorobutanal, their dibromo analogs, or to the corresponding 2-halopropenals and 2-halobutenals should therefore be considered as candidate promutagens.

[]-azoxybis(methylene) bis(3-chlorobenzoate): potent mutagen from reaction of hexamethylphosphoramide, -methylhydroxylamine and []-nitrosomethane dimer with 3-chloroperoxybenzoic acid

Abstract [ E ]-Azoxybis(methylene) bis(3-chlorobenzoate), an exceptionally potent mutagen (3050 revertants/nmol) in the Salmonella typhimurium (strain TA100) assay, is formed in trace ( E ]-nitrosomethane dimer on treatment of hexamethylphosphoramide or N -methylhydroxylamine with 3-chloroperoxybenzoic acid.