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1901. Insecticide synergists inhibit mammalian microsomal enzymes
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BIOCHEMICAL PHARMACOLOGY, CANCER RESEARCH
[Despite the limited results so far obtained with this new technique it would appear to represent a considerable step forward in the translation of eye-irritancy data from animals to man.]
BIOCHEMICAL P H A R M A C O L O G Y 1901. Insecticide synergists inhibit mammalian microsomal enzymes Jaffe, H., Fujii, K., Sengupta, M., Guerin, H. & Epstein, S. S. (1968). In vivo inhibition of mouse liver microsomal hydroxylating systems by methylenedioxyphenyl insecticidal synergists and related compounds. Life Sci. 7, 1051. Compounds containing the methylenedioxyphenyl (MDO) group are sometimes used as pyrethrin synergists. They are, however, liver toxins and may accentuate the effects of carcinogens by retarding their metabolism in the body (Cited in F.C.T. 1965, 3, 857). Synergistic effects in insects are believed to be produced by blockage of the microsomalenzyme system concerned with the detoxication of the insecticide. The effects of these and related compounds on two mammalian detoxicating enzymes are described in this paper. An aqueous suspension of each compound was injected intraperitoneally into a group of adult mice in a single dose of 160 mg/kg, the mice were killed 1 hr later and the hydroxyfating activity of the crude microsomal fractions of the homogenized livers was assayed, using dimethylaminopyrine and hexobarbitone as substrates. Of 27 compounds tested, including 13 natural products occurring in essential oils, 7 caused moderate to strong inhibition of dimethylaminopyrine and hexobarbitone hydroxylases under these conditions. These were eugenol, n-propyl isome, 3,4-MDO-n-butoxyethoxyethylcarbamate, methyl eugenol, sesamex, piperonyl cyclonene and piperonyl butoxide. In addition, apiol, isosafrole and dihydrosafrole were all moderate inhibitors of hexobarbitone hydroxylation, while safrole and dihydrosafrole strongly inhibited dimethylaminopyrine hydroxylation and apiol and isosafrole had little effect on this enzyme. Safrole only weakly affected the hexobarbitone enzyme. With the exception of dihydrosafrole, the simple MDO derivatives were not enzyme inhibitors, while some compounds lacking this moiety were, hence the inhibitory activity does not appear to be specifically associated with the MDO grouping. In general compounds with proven insecticidal synergistic activity were also effective inhibitors of the mammalian enzymes. lit is questionable whether these pyrethrin synergists would evoke changes in microsomalenzyme activity in man under the practical conditions of usage. There is, in any case, the possibility that the enzyme-inhibitory potential of these compounds is counteracted by the stimulatory effects of other compounds, such as organochlorine pesticides and drugs, to which man may simultaneously be exposed.]
CANCER RESEARCH 1902. Implants in the bladder Clayson, D. B., Pringle, J. A. S., Bonser, G. M. & Wood, M. (1968). The technique of bladder implantation: Further results and an assessment. Br. J. Cancer 22, 825. Prolonged contact between the test chemical and the target tissue is essential in carcinogenicity tests. The bladder-implantation technique used in the mouse is designed to achieve
BIOCHEMICAL PHARMACOLOGY, CANCER RESEARCH
[Despite the limited results so far obtained with this new technique it would appear to represent a considerable step forward in the translation of eye-irritancy data from animals to man.]
BIOCHEMICAL P H A R M A C O L O G Y 1901. Insecticide synergists inhibit mammalian microsomal enzymes Jaffe, H., Fujii, K., Sengupta, M., Guerin, H. & Epstein, S. S. (1968). In vivo inhibition of mouse liver microsomal hydroxylating systems by methylenedioxyphenyl insecticidal synergists and related compounds. Life Sci. 7, 1051. Compounds containing the methylenedioxyphenyl (MDO) group are sometimes used as pyrethrin synergists. They are, however, liver toxins and may accentuate the effects of carcinogens by retarding their metabolism in the body (Cited in F.C.T. 1965, 3, 857). Synergistic effects in insects are believed to be produced by blockage of the microsomalenzyme system concerned with the detoxication of the insecticide. The effects of these and related compounds on two mammalian detoxicating enzymes are described in this paper. An aqueous suspension of each compound was injected intraperitoneally into a group of adult mice in a single dose of 160 mg/kg, the mice were killed 1 hr later and the hydroxyfating activity of the crude microsomal fractions of the homogenized livers was assayed, using dimethylaminopyrine and hexobarbitone as substrates. Of 27 compounds tested, including 13 natural products occurring in essential oils, 7 caused moderate to strong inhibition of dimethylaminopyrine and hexobarbitone hydroxylases under these conditions. These were eugenol, n-propyl isome, 3,4-MDO-n-butoxyethoxyethylcarbamate, methyl eugenol, sesamex, piperonyl cyclonene and piperonyl butoxide. In addition, apiol, isosafrole and dihydrosafrole were all moderate inhibitors of hexobarbitone hydroxylation, while safrole and dihydrosafrole strongly inhibited dimethylaminopyrine hydroxylation and apiol and isosafrole had little effect on this enzyme. Safrole only weakly affected the hexobarbitone enzyme. With the exception of dihydrosafrole, the simple MDO derivatives were not enzyme inhibitors, while some compounds lacking this moiety were, hence the inhibitory activity does not appear to be specifically associated with the MDO grouping. In general compounds with proven insecticidal synergistic activity were also effective inhibitors of the mammalian enzymes. lit is questionable whether these pyrethrin synergists would evoke changes in microsomalenzyme activity in man under the practical conditions of usage. There is, in any case, the possibility that the enzyme-inhibitory potential of these compounds is counteracted by the stimulatory effects of other compounds, such as organochlorine pesticides and drugs, to which man may simultaneously be exposed.]
CANCER RESEARCH 1902. Implants in the bladder Clayson, D. B., Pringle, J. A. S., Bonser, G. M. & Wood, M. (1968). The technique of bladder implantation: Further results and an assessment. Br. J. Cancer 22, 825. Prolonged contact between the test chemical and the target tissue is essential in carcinogenicity tests. The bladder-implantation technique used in the mouse is designed to achieve