The conversion of some monoalkylhydrazines to their corresponding hydrocarbons by a hepatic microsomal enzyme system in rat Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/b8515s315

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  • An aspect of the metabolism of monoalkylhydrazines has been investigated using both intact rats and rat liver microsomal enzyme preparations. Intact rats respired propane and n-butane on administration of 0.3-0.5 mmoles of isopropyl- and n-butylhydrazine, respectively. Based upon dose administered, a five to ten percent yield of hydrocarbon was obtained. In vitro experiments were conducted to further characterize the reaction. The conversion of alkylhydrazines to alkanes occurred predominantly in the microsomal fraction of liver cells. All of the simple monoalkylhydrazines, methyl-, ethyl-, n-propyl-, isopropyl- and n-butylhydrazine , were converted to the corresponding alkanes at a rate of ca. 20 mμmoles/120 min/10 mg of microsomal protein. Other substrates yielding methane were the azo derivative of Procarbazine (N-isopropyl-α-[2- methylhydrazino]-p-toluamide), the azoxy derivative of Procarbazine and methylazoxymethanol acetate. The reaction specifically required oxygen, NADPH and liver microsomes. Rat and guinea pig microsomal preparations converted the alkylhydrazines to alkanes at a rate higher than bovine, porcine and ovine microsomal preparations. Various parameters typical of enzyme reactions indicated that the reaction was enzymic. The apparent Michaelis constant for ethylhydrazine was found to be 4.5 x 10⁻⁵M with a maximal enzyme velocity of 32.0 mμmoles of ethane/120 min/10 mg of microsomal protein. The enzymic reaction was linear with time to 120 min, with microsomal protein to 10 mg and with NADPH to 30 μmoles. Some enzyme inhibitors, p-chloromercuribenzoate and N-ethylmaleimide, caused 50% inhibition at 10⁻⁶M and 10⁻⁵M, respectively. Cyanide, carbon monoxide, chelating agents and a mixed-function oxidase inhibitor (SKF 525-A) had no great effect on the enzyme reaction. Cytochromes b₅ and P₄₅₀ did not appear to play a role in the reaction. The lack of correlation between loss of enzyme activity and cytochrome content during tryptic digestion, lack of enzyme in- duction with P₄₅₀ induction by phenobarbital and 3-methylcholanthrene administration and lack of correlation between b₅ content and enzyme activity on lipase solubilization indicate strongly that cytochrome P₄₅₀ and b₅ are not required for alkylhydrazine oxidase activity. Only a marginal purification could be performed. A methylhydrazine derivative, Procarbazine, was converted to the azo derivative with the same microsomal preparations and conditions. The possibility of an alkyldiazene (alkyldiimide) intermediate is discussed.
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