Effect of 3-methylcholanthrene on the development of aortic lesions in mice.

The effect of a carcinogen, 3-methylcholanthrene (3-MC), on the formation and growth of atherosclerotic lesions in mice was examined. Increasing doses of 3-MC from 15 to 1500 micrograms/kg increased the number and size of lipid-staining lesions in the aorta of AKXL-38a mice that were fed an atherogenic diet for 8 weeks. The number of lesions per mouse was 0.85 +/- 0.19 (SE) for animals treated with 3-MC (150 micrograms/kg) compared to 0.10 +/- 0.10 lesions/mouse for animals given solvent rather than 3-MC. The progression of lesions over time from 5 to 18 weeks showed that 3-MC-treated mice also differed from controls in the size of lesions. The total score per mouse at 18 weeks of atherogenic diet, based on the number of lesions and the size of each lesion, indicated by a score of 1 to 4, was 4.31 +/- 0.71 for 3-MC-treated animals and 2.67 +/- 0.74 for animals given solvent. The effect of 3-MC treatment could be observed at 18 weeks even though the entire dose of 3-MC was given during the first week on the atherogenic diet. These experiments do not distinguish whether 3-MC affects atherosclerotic lesions by acting as a mutagen or by some other mechanism. The composition of an atherogenic diet that produces lesions in mice without high mortality is given as well as a comparison of different methods of evaluating lesion formation.

Seasonal variation of aryl hydrocarbon hydroxylase activity in human lymphocytes.

A seasonal variation was observed when aryl hydrocarbon hydroxylase (AHH) activity was measured in the cultured lymphocytes of 977 donors over a period of 2 1/2 years. The variation was strongest in AHH activity induced by 3-methylcholanthrene and was less apparent for AHH activity in lymphocytes grown without any inducer. The period of the seasonal variation is 1 year, and maximal induced AHH activity occurs during late summer and early fall with minimal activity 6 months later. Based on the average of all individuals tested during the highest and lowest weeks, induced AHH activity can be as much as 10-fold higher during the peak season. It is not possible to tell from these experiments whether the seasonal variation is tissue specific, occurring only in lymphocytes, or characteristic of microsomal oxidases in other tissues as well.

Aryl hydrocarbon hydroxylase in persons with lung or laryngeal cancer.

To test whether the distribution of AHH inducibility is shifted toward the high end of the range in patients who had lung and laryngeal cancer, we measured this trait in 59 patients (32 lung and 27 laryngeal) who had resectable tumors and had been disease-free for a period of time. The advantage of selecting patients who were free of clinical disease was that measurement of their AHH inducibility should not have been affected by the disease state. Patient and control populations showed no difference in basal and induced AHH activity of AHH inducibility. The mean AHH inducibility in patients who had lung cancer was 3.20 +/- 0.20; in patients who had laryngeal cancer 2.96 +/- 0.18, and for all controls 3.29 +/- 0.04 (no significant difference at p = 0 05). Further analysis of the distribution of AHH inducibility in the patient group compared to controls showed no suggestion of a shift toward the higher end of the range in patients who had lung and laryngeal cancer.

Inhibitor of phospholipase A2 blocks eicosanoid and platelet activating factor biosynthesis and has topical anti-inflammatory activity.

The effect of a phospholipase A2 (PLA2) inhibitor on leukotriene, prostaglandin and platelet activating factor (PAF) biosynthesis in isolated cells and in vivo was determined. BMS-181162, [4(3'-carboxyphenyl)-3,7-dimethyl-9(2",6",6"-trimethyl-1"- cyclohexenyl)2Z,4E,6E,8E-nonatetraenoic acid], reversibly inhibited the 14-kdalton PLA2 purified from human synovial fluid with an IC50 of 8 microns. In A23187-stimulated human polymorphonuclear leukocytes (PMNs), BMS-181162 blocked arachidonic acid release with an IC50 of 10 microns. Leukotriene B4 and PAF biosynthesis in these cells was also inhibited. In a phorbol ester-induced chronic mouse skin inflammation model, topically applied BMS-181162 markedly lowered the tissue levels of leukotriene B4 and prostaglandin E2 and dose-dependently inhibited leukocyte infiltration (ED50 = 180 micrograms per ear). BMS-181162 is an inhibitor of PLA2 and may prove to be a useful tool in the delineation of the role of PLA2 in the inflammatory process.