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Adducts of dienochlor miticide with glutathione, glutathione S-transferases, and hemoglobins.

Dienochlor (Pentac) (C10Cl10) has been used for 30 years as a miticide with little knowledge of its mode of action or metabolic fate except that it is quickly degraded by rats. This study examines the reactions of dienochlor with GSH and proteins as models for its metabolism and interactions with tissues. Dienochlor reacts rapidly with 1.0 mM GSH in phosphate buffer (pH 7.4) at 37 degrees C (t1/2 approximately 11 min) as analyzed by UV/visible spectroscopy and HPLC, yielding a series of more than a dozen adducts. Octachlorofulvalene (C10Cl8), a candidate intermediate, also reacts to give the same apparent products (t1/2 < 0.2 min as above); however, its intermediacy in the dienochlor reaction was not established. Isolation and MS analyses characterized two isomeric C10H2Cl(SG)5 adducts and a C10H2(SG)6 derivative; these products react further in the presence of GSH to yield two even more polar adducts. Cysteine and N-acetylcysteine also react rapidly with dienochlor whereas GSSG and several non-thiol amino acids are much less reactive. Purified GSH S-transferases (GSTs) and hemoglobins, each from six species of mammals including humans, are extensively labeled in vitro by [14C]dienochlor to form adducts separable by gel electrophoresis and HPLC. [14C]Dienochlor readily derivatizes rat liver GSTs even in cytosol and in the presence of high GSH levels. The potency of dienochlor for inhibition of GST activity is maintained or enhanced upon conversion to GSH adducts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

Structure-activity relationships for the glutathione conjugation of 2-substituted 1-chloro-4-nitrobenzenes by rat glutathione S-transferase 4-4.

In the present study structure--activity relationships (SAR's) are described for the experimentally determined kinetic parameters (Km, kappa cat, and kappa cat/Km) of the GST 4-4-catalyzed reaction between GSH and 10 2-substituted 1-chloro-4-nitrobenzenes. Steric, lipophilic, and electronic parameters were correlated with the kinetic parameters. Moreover, charge distributions and several energy values were calculated for the substrates and the corresponding Meisenheimer intermediates with MeS- as a model nucleophile for the thiolate anion of GSH and used in the regression analyses. The correlations obtained were compared with the corresponding SAR's for the base-catalyzed GSH conjugation reaction at pH 9.2. A high correlation coefficient was found between the kinetic parameter kappa s for the base-catalyzed reaction and the Hammett substituent constant (sigma p). Much lower correlation coefficients were obtained with kappa cat and sigma p and with kappa cat/Km and sigma p. Moreover, the reaction constant rho was significantly higher for the base-catalyzed than for the enzyme-catalyzed reaction. Also, high correlations were found between the kinetic parameters and the charges on the p-nitro substituent in the substrates. When kappa s was plotted against these charges, a linear relationship was found in which the slope was larger than the slope of a corresponding plot with kappa cat/Km. The Hammett sigma p can be divided into an inductive (F) and a resonance (R) component. With multiple regression between the kinetic parameters and F and R, higher correlation coefficients were obtained than with sigma p alone. Our observations suggest that the transition states for the base-catalyzed and the GST 4-4-catalyzed GSH conjugation reaction are different. Moreover, single classical physiochemical and computer-calculated molecular parameters and combinations of them can be an alternative approach for examining SAR's for spontaneous and GST-catalyzed GSH conjugation reactions.

Animals↗