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M C Kirk

Publications and source records attributed to M C Kirk.

31 records · Page 2Linked to original sources
PubMed1982

Refined carbohydrate as a contributing factor in reactive hypoglycemia.

To assess the effects of diet on symptoms in patients with idiopathic reactive hypoglycemia, we obtained by dietary recall histories the dietary composition from eight of these patients. The data obtained represented the dietary content of each individual before and after instruction on a diet containing 100 gm of carbohydrate daily. Neither the percentage of carbohydrate or fat nor the total grams of protein or fat changed significantly after dietary instruction. In contrast, the percentage of refined carbohydrate decreased (P = .003) and the percentage of protein increased (P = .003). The total grams of refined carbohydrate and total carbohydrate both decreased significantly (P = .01 and .05, respectively), but the fall in refined carbohydrate (from 147 to 20 gm) accounted for the entire fall in total dietary carbohydrate. All values except those of refined carbohydrate were within 95% confidence limits of the average diet in Western culture. Despite continuing intake of a normal quantity of total carbohydrate (mean, 221 gm), all patients had symptomatic improvement. These data suggest that reducing the amount of dietary refined carbohydrate may be important in the treatment of idiopathic reactive hypoglycemia, and that quantitative reduction in total carbohydrate may be of lesser importance.

Adult↗
PubMed1982

Formation of the cross-link 1-[N3-deoxycytidyl),2-[N1-deoxyguanosinyl]ethane in DNA treated with N,N'-bis(2-chloroethyl)-N-nitrosourea.

The cross-linked dinucleoside, 1-[N3-deoxycytidyl],2-[N1-deoxyguanosinyl]ethane, has been isolated from DNA which has been exposed to N,N'-bis(2-chloroethyl)-N-nitrosourea. It is probable that this structure is responsible for the interstrand cross-linking observed previously by physical methods. The modification is unique in that it cross-links DNA through two base-pairing positions and probably arises through the transfer of a chloroethyl group to one of the bases followed by a second reaction of this group with the other strand of DNA. Initial attack could be at the N3 position of deoxycytidine, the N1 position of deoxyguanosine, or possibly the O6 position of deoxyguanosine. Attack at the O6 position of deoxyguanosine would require an internal cyclization with the N1 position of deoxyguanosine before secondary reaction with the N3 position of deoxycytidine but would explain resistance to N,N'-bis(2-chloroethyl)-N-nitrosourea in cells capable of removing substituents on the O6 position of guanine.

Animals↗
PubMed1981

Metabolism and macromolecular binding of the carcinogen Michler's ketone in rats.

1. Studies on the metabolism of 14C-Michler's ketone (4,4'-bis-(dimethylamino)[carbonyl- 14C]benzophenone) in rats have revealed that this carcinogen is subject to demethylation, ring-hydroxylation and N-acetylation after adjacent methyl groups have been removed. 2 As identified by mass spectral analysis, microsomal metabolites are the mono-, di-, tri- and tetra-demethylated derivatives. 3. The major metabolites appearing in the bile are the di- and tri-demethylated derivatives and the N-acetylated tetra-demethylated compound; minor metabolites, tentatively identified, are the ring-hydroxylated derivatives of di- and tri-demethylated Michler's ketone and of N-acetylated tri- and tetra-demethylated Michler's ketone. 4. The major urinary metabolite is tentatively identified as a ring-hydroxylated derivative of N-acetylated, di-demethylated Michler's ketone; a minor urinary metabolite lacks the hydroxyl group. 5. Injection of 14C-Michler's ketone into rats resulted in the irreversible binding of radioactivity to liver proteins. 6. When the rats were pretreated with phenobarbital, this binding was increased and extended to proteins of some other tissues and to DNA and RNA of liver and DNA of kidney.

Animals↗
PubMed1975

Isolation and mass spectral identification of blood metabolites of cyclophosphamide: evidence for phosphoramide mustard as the biologically active metabolite.

Thin-layer chromatography and mass spectrometry were used to isolate and identify cyclophosphamide metabolites present in blood of mice. Blood was removed 5, 15, 30 and 45 minutes after intraperitoneal administration and extracted with chloroform followed by methanol. Thin-layer chromatography of the two extracts and the residual solid with or without prior methylation, collection of resulting alkylating components, determination of radioactivity and mass spectral analysis, served to identify cyclophosphamide, 4-ketocyclophosphamide, alcophosphamide, N-dechloroethylcyclophosphamide, carboxyphosphamide, phosphoramide mustard and nor-HN2. The absence of detectable levels of 4-hydroxycyclophosphamide or aldophosphamide in the blood of cyclophosphamide-treated mice suggests that cyclophosphamide is converted rapidly in the liver to carboxyphosphamide, 4-ketocyclophosphamide, phosphoramide mustard and nor-HN2. Direct administration of synthetic 4-hydroxycyclophosphamide to mice and extraction of blood with chloroform demonstrated the recovery of this metabolite in vivo. Analysis of extracts of blood from mice treated with phosphoramide mustard indicated the presence of nor-HN2, 3-(2-chloroethyl)-1,3-oxazolidin-2-one and unchanged drug. Consideration of blood levels, cytotoxicity and alkylating activity of metabolites identified, in or inferred from, this study, implicates phosphoramide mustard as a leading condidate for the biologically active form of cyclophosphamide.

Animals↗
PubMed1975

Decomposition of N-(2-chloroethyl)-N-nitrosoureas in aqueous media.

A reinvestigation of the aqueous decomposition of N-(2-chloroethyl)-N-nitrosoureas has shown that their mode of decomposition is dependent upon whether or not the solution is buffered at or near physiological pH. In distilled water, the 2-chloroethyl compounds decompose with the loss of 1 mol, or slightly less, of chloride ion per mole in nitrosourea and the formation of acetaldehyde and 3-4% of 2-chloroethanol. In buffer, the yield of 2-chloroethanol increases to 0.3-0.6 mol per mole of nitrosourea, the yield of chloride ion decreases to 0.5 mol per mole of nitrosourea, and the yield of acetaldehyde decreases to 0.1-0.4 mol per mole of nitrosourea. Evidence for the formation of the vinyl cation, a possible precursor of acetaldehyde, in these reactions is presented. In contrast to the results obtained with the N-(2-chloroethyl)-N-nitrosoureas, the decomposition of N,N'-bis(2-fluoroethy)-N-nitrosourea in distilled water gave almost 1 mol of 2-fluoroethanol per mole of nitrosourea and only 0.04 mol of acetaldehyde per mole of nitrosourea.

Carmustine↗
PubMed1975

Isolation of cis- and trans-4-methylcyclophosphamide and antitumor evaluation in vivo.

4-Methylcyclophosphamide was synthesized and separated into cis and trans isomers by column chromatography. Isolation of these isomers permitted individual evaluation against murine leukemia L1210 in vivo and assessment of possible differences in antileukemic activity. Results indicate no appreciable difference in activity of the isomers, suggesting essentially equal facility for activation by mouse liver microsomes in vivo.

Animals↗
PubMed1975

Microsomal metabolism of nitrosoureas.

N, N-Bis (2-chloroethyl)-N-nitrosourea (BCNU) is a substrate for a microsomal enzyme of mouse liver. The reaction requires NADPH, and the product is 1, 3-bis (2-chloroethyl) urea. This activity is also found in mouse lungs but not in several other tissues. With reaction conditions under which BCNU is not chemically degraded, the Km for BCNU with liver microsomes is 1.7 mM; nicotine is a competitive inhibitor with a Ki of 0.6 mM. N-Methyl-N-nitrosourea is denitrosated in a similar reaction. N- (2-Chloroetyhy)- N-cyclohexyl-N-nitrosourea and N-(2-chloroethyl)-N-(trans-4-methylcyclohexyl)-N-nitrosourea are also substrates for microsomal enzymes, but the products of these reactions are ring-hydroxylated derivatives. The Km value for N-(2-CHLOROETHYL)-N-cyclohexyl-N-nitrosourea is 3.0 mM and that for N-(2-chloroethyl)-N-(trans-4-methylcyclohexyl)-N-nitrosourea is 1.0 mM. The hydroxylase activity is also present in lungs, but not in the other mouse tissues. The rates of microsomal metabolism of BCNU, N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea, and N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea, and N-(2-chloroethyl-N-(trans-4-methylcyclohexyl)-N-nitrosourea are fast enough to allow metabolism of large portions of administered doses before chemical decomposition of the drugs occurs.

Animals↗