Biomedical subjects

M M Milks

Publications and source records attributed to M M Milks.

6 recordsLinked to original sources

PubMed1991

Metabolism of arachidonic acid in neutrophils from alloxan-diabetic rabbits.

The production of 5-lipoxygenase products from arachidonic acid was investigated in polymorphonuclear leukocytes (PMNL) isolated from non-diabetic and alloxan-induced diabetic rabbits: (i) production of 5-hydroxyeicosatetraenoic acid, leukotriene B4, and the two 6-trans-leukotriene B4 isomers were significantly decreased in the PMNL of diabetic rabbits when compared to non-diabetic rabbits; (ii) production of LTB4 and 5-HETE from diabetic PMNL required the addition of Ca2+ and A23187 to a greater degree than control incubations; and (iii) the availability of substrate in the PMNL of diabetics was not a limiting factor for 5-lipoxygenase product formation. Alternative pathways of arachidonic acid metabolism were also evaluated: the recovery of exogenous leukotriene B4 and 5-hydroxyeicosatetraenoic acid were identical using PMNL from control and diabetic rabbits and peptido-leukotrienes were not detected by radioimmunoassay. The data suggest that the activity of 5-lipoxygenase and the production of 5-hydroperoxyeicosatetraenoic acid in the diabetic PMNL may be limiting factors since the formation of leukotriene B4, leukotriene B4 isomers, and 5-hydroxyeicosatetraenoic acid are depressed in PMNL of diabetic rabbits. Alternative pathways do not account for the conversion of arachidonic acid to other products nor are the elimination pathways for LTB4 and 5-HETE different. Decreased formation of 5-hydroxyeicosatetraenoic acid and leukotriene B4 could predispose diabetic subjects to infection due to a decrease in mediators leading to the local accumulation of PMNL in the inflammatory response.

Animals↗

PubMed1985

Metabolism of 4,7,10,13,16-docosapentaenoic acid by human platelet cyclooxygenase and lipoxygenase.

Washed human platelets are shown to metabolize 4,7,10,13,16-docosapentaenoic acid into three major metabolites which were purified by reverse-phase HPLC. The mass spectra of the methyl ester-trimethylsilyl ether and ethyl ester-trimethylsilyl ether of compound A established it as delta 4-dihomo-thromboxane B2. Compound B was shown to be 14-hydroxy-4,7,10,12-nonadecatetraenoic acid, which is analogous to 12-hydroxy-5,8,10-heptadecatrienoic acid from arachidonic acid. Compound C was produced via an indomethacin-insensitive pathway and was identified as 14-hydroxy-4,7,10,12,16-docosapentaenoic acid. Time- and substrate-dependent studies showed that compounds A,B and C were produced approximately 10,15 and 65% of the extent to which thromboxane B2, 12-hydroxy-5,8,10-heptadecatrienoic acid and 12-hydroxy-5,8,10,14-eicosatetraenoic acid were produced, respectively, from arachidonic acid.

Arachidonic Acid↗

PubMed1985

The effects of selenium on the emergence of aflatoxin B1-induced enzyme-altered foci in rat liver.

The effects of selenium on the emergence of aflatoxin B1 (AFB1)-induced enzyme-altered foci were studied in male Sprague-Dawley rats. Animals were fed a selenium-deficient diet and supplemented with 5.0, 2.0, and 0.2, or 0 ppm selenium in drinking water for 3 weeks prior to initiation with 2.0 mumol/kg AFB1. After a 1-week period of selenium normalization, the animals were placed on a diet of ordinary rat chow, and were administered a promoting regimen of 500 ppm phenobarbital in drinking water for 1 week, after which time each rat received a two-thirds partial hepatectomy. The promoting regimen of phenobarbital in tap water was then reduced to 100 ppm and continued for 7 weeks. Subsequently, the rats were sacrificed, their livers excised, and fresh frozen sections prepared and stained histochemically to demonstrate areas of gamma-glutamyl transpeptidase (GGT) activity. Selenium supplementation was observed to diminish the induction of GGT-positive foci, especially at the 5.0-ppm level. These data suggest that selenium is able to protect against the hepatocarcinogenic effects of AFB1 in the rat, and that the enzyme-altered foci bioassay may be a useful technique in assessing the interaction of selenium on the process of hepatocarcinogenesis.

Aflatoxin B1↗

PubMed1985

Hexacarbon neuropathy: tracking a toxin.

This paper will present the progression of hexacarbon studies which followed the investigation of circumstances surrounding the occurrence of peripheral neuropathy in an occupational setting. The identification of methyl n-butyl ketone as the neurotoxin led to systematic studies of the biotransformation and mechanism of neurotoxicity. A consistent line of evidence showed that the neurotoxic potential of hexacarbons is directly related to the formation of the gamma-diketone metabolite, 2,5-hexanedione. The precise nature of the chemical interaction at the neurofilament is the subject of continuing investigation.

Animals↗

PubMed1984

Trichloroethylene effects on the formation of enzyme-altered foci in rat liver.

The initiating and promoting effects of trichloroethylene in rat liver were investigated using the enzyme-altered foci bioassay. The incidence of gamma-glutamyl transpeptidase (GGT)-positive foci was used as an early histochemical marker of putative preneoplastic hepatocytes. A single PO dose of trichloroethylene (490 mg/kg) was administered in corn oil to rats which had been partially hepatectomized 24 h previously. Three days following gavage with the chlorinated hydrocarbon the rats were promoted with an 8-week regimen of 500 ppm phenobarbital in drinking water. This protocol is known to induce enzyme-altered foci in the livers of animals which have received an initiating dose of a genotoxic carcinogen. Trichloroethylene was not found to induce GGT-positive foci under these conditions. Additionally, groups of rats were partially hepatectomized, initiated with N-nitrosodiethylamine (30 mg/kg; PO) and administered five times weekly doses of 200 mg trichloroethylene per rat in order to investigate the promoting activity of the chlorinated hydrocarbon in rat liver. No significant promoter effects were observed with trichloroethylene, although the results in this case were somewhat equivocal. The findings of these investigations are taken as partially supportive of an epigenetic, cytotoxic mechanism of tumorigenic action of trichloroethylene.

Animals↗

PubMed1982

Methapyrilene effects on initiation and promotion of gamma-glutamyl-transpeptidase positive foci in rat liver.

The initiating and promoting effects of methapyrilene were evaluated using the hepatic enzyme-altered foci bioassay. Male Sprague-Dawley rats were partially hepatectomized and 24 hours later were administered either methapyrilene or nitrosodiethylamine by oral gavage. Subsequently, the animals were promoted with 500 ppm2 phenobarbital or 200 ppm methapyrilene in drinking water for eight weeks. Fresh frozen sections of liver were then stained and scored for gamma-glutamyl-transpeptidase (GGT)-positive foci. Methapyrilene, when tested as the nominal initiator at a single dose of 50 mg/kg or at two doses of 130 mg/kg and promoted by phenobarbital, did not induce foci above background levels. However, when substituted for phenobarbital as the promoting agent following nitrosodiethylamine initiation, methapyrilene enhanced enzyme-altered foci formation to an equal or greater extent than did the promoter phenobarbital. These results suggest that the carcinogenic effects of methapyrilene may be related to its ability to enhance hepatic tumorigenesis.

Aminopyridines↗