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The metabolism of d-limonene
474
Flavourings, solvents and sweeteners, Antioxidants
glands was observed in the skin at the site of development of both types of tumour. Despite the fact that both types were characterized as carcinomas, gross examination of the internal organs revealed no evidence of nodules suggestive of metastasis. No external tumours were seen in the control animals. Dhis study is certainly more worrying than those reported previously, and presumably formed the basis of the recent US ban, on the grounds that the colouring used was certifiable FD & C Violet No. 1 (Food
Chemical News 1973,15(4) 3).A possibleexplanation
for the difference in results between this and the BIBRA mousestudy may lie in the much higherdietary levelsadministeredin the presentcase(5% comparedwith 0.35x), with consequentingestionot much greater quantitiesnot only of the colouring but also of its contaminants.It is to be hoped that an FDA study, undertakenasa result of the Japanese findings, will resolvethe whole question.]
FLAVOURINGS, SOLVENTS AND SWEETENERS perillic acid-8,9-dioland 8-hydroxy-p-menth-l-ene-9yl-/&@ucopyranosiduronic acid were found. HowIgimi, H., Nishimura, M., Kodama, R. & Ide, H. ever, at leasttwo compoundspresentin rabbit urine, and p-mentha-l,&dien-lO-yl(1974).Studieson the metabolismof d-limonene(p- p-mentha-1,8-dien-l&o1 acid werenot presentin rat mentha-1,8-diene). I. The absorption,distribution and /?-D-glucopyranosiduronic urine. A tentative schemefor the metabolismof dexcretion of d-limonenein rats. Xenobiotica 4, 77. limonenein the rabbit has beendeducedto account Kodama,R., Noda, K. & Ide, H. (1974).Studieson for thesemetabolites. the metabolismof d-limonene(p-mentha-1,8-diene). The rat studiesshowedthat d-limonenewasrapidly II. The metabolicfate of d-limonenein rabbits.Xeno- absorbedfrom the gastro-intestinaltract, with blood levelsof radioactivity reachinga maximum2 hr after biotica 4, 85. dosingand remaininghigh for 10 hr. A similar patAlthough monoterpenes,of which the title com- tern was Seenin the liver and kidneys. Elimination pound is an example,are widely distributed in the from the body was rapid; little activity was left at natural environmentand find extensiveindustrial use 48 hr, and autoradiographyshowedno significantacasflavouring agentsin foodsand cosmetics,little sys- cumulationat this time in any organ. The principal tematic information about their metabolic fate is route of eliminationwas the urine and over 60”/, of available.The potential clinical useof d-limoneneas the administereddosewas eliminatedby this route an agent for dissolvingcholesterolgallstones(Nishi- in 48 hr. Biliary excretion amountedto 25% of the mura, Jup. J. Surg. 1972,2, 62) prompted this thor- dosewithin 24 hr, but as faecalexcretionof radipactiough study of the absorption,metabolismand excre- vity in non-cannulatedanimalswas low, it appears tion of d-limonenein rats and its metabolic fate in that biliary metaboliteswere reabsorbedprior to elithe rabbit. mination.The major biliary metabolitewas identified In both studies,the animalsweregiven 14C-labelled as 8-hydroxy-p-menth-1-en-9-yl-P-D-glucopyranosidd-limoneneorally by stomachtube, in a singledose uranic acid, and the effect of this compoundon the of the order of 800mg/kg, and a number of urinary solubilizationof cholesterolgallstonesis under invesmetaboliteswere isolatedand identified. In both rat tigation. and rabbit urine, perillic acid, p-menth-l-ene-$Pdiol, 2870.The metabolismof d-limonene
ANTIOXIDANTS
2871.Propyl gallate:A clandestinesensitizer? Kahn, G., Phanuphak,P. & Claman,H. N. (1974). Propyl gallate-contact sensitization and orally-inducedtolerance.Archs Derm. 109, 506. Propyl gallate (PG) is extensively used as an antioxidant in fats to prevent the developmentof rancidity. It appearsthat no reportsof contact sensitization to PG have appearedin the USA despiteits use there since1947,but evidenceis presentedthat induced immunologicaltolerance may explain this absenceof overt reactions. Ten adult subjectsapplied20%PG in 70%ethanol to the skin of the forearmdaily for 24 days,or until rednessor itching occurred. No subject.developed signsof reaction during the first 14 days but during
wk 3 and 4 five participantscomplainedof pruritus and erythema. These effects were minimal in three casesand subsidedwithin a few days, while in the other two the rash spread to the upper arm neck and trunk within 34 days despite avoidance of further exposureto PG. Two of the mildly sensitized reactors.and 25 non-sensitizedcontrols were then treatedwith 2% PG and 2% lauryl gallatepatch tests for 48 hr. Both sensitizedpersonshad mild positive reactionsto both esterswhile the controls showed no response. In further tests,in guinea-pigs,intradermal injections of @l ml of 5% PG in Freund adjuvant given threetimeson alternatedaysconferredstrongsensitization lasting at least 3 months.The animalscrossreactedto lauryl gallate(weakly) but not to pyrogal101,gaIlic acid or methyl gallate. Three paintings of
Flavourings, solvents and sweeteners, Antioxidants
glands was observed in the skin at the site of development of both types of tumour. Despite the fact that both types were characterized as carcinomas, gross examination of the internal organs revealed no evidence of nodules suggestive of metastasis. No external tumours were seen in the control animals. Dhis study is certainly more worrying than those reported previously, and presumably formed the basis of the recent US ban, on the grounds that the colouring used was certifiable FD & C Violet No. 1 (Food
Chemical News 1973,15(4) 3).A possibleexplanation
for the difference in results between this and the BIBRA mousestudy may lie in the much higherdietary levelsadministeredin the presentcase(5% comparedwith 0.35x), with consequentingestionot much greater quantitiesnot only of the colouring but also of its contaminants.It is to be hoped that an FDA study, undertakenasa result of the Japanese findings, will resolvethe whole question.]
FLAVOURINGS, SOLVENTS AND SWEETENERS perillic acid-8,9-dioland 8-hydroxy-p-menth-l-ene-9yl-/&@ucopyranosiduronic acid were found. HowIgimi, H., Nishimura, M., Kodama, R. & Ide, H. ever, at leasttwo compoundspresentin rabbit urine, and p-mentha-l,&dien-lO-yl(1974).Studieson the metabolismof d-limonene(p- p-mentha-1,8-dien-l&o1 acid werenot presentin rat mentha-1,8-diene). I. The absorption,distribution and /?-D-glucopyranosiduronic urine. A tentative schemefor the metabolismof dexcretion of d-limonenein rats. Xenobiotica 4, 77. limonenein the rabbit has beendeducedto account Kodama,R., Noda, K. & Ide, H. (1974).Studieson for thesemetabolites. the metabolismof d-limonene(p-mentha-1,8-diene). The rat studiesshowedthat d-limonenewasrapidly II. The metabolicfate of d-limonenein rabbits.Xeno- absorbedfrom the gastro-intestinaltract, with blood levelsof radioactivity reachinga maximum2 hr after biotica 4, 85. dosingand remaininghigh for 10 hr. A similar patAlthough monoterpenes,of which the title com- tern was Seenin the liver and kidneys. Elimination pound is an example,are widely distributed in the from the body was rapid; little activity was left at natural environmentand find extensiveindustrial use 48 hr, and autoradiographyshowedno significantacasflavouring agentsin foodsand cosmetics,little sys- cumulationat this time in any organ. The principal tematic information about their metabolic fate is route of eliminationwas the urine and over 60”/, of available.The potential clinical useof d-limoneneas the administereddosewas eliminatedby this route an agent for dissolvingcholesterolgallstones(Nishi- in 48 hr. Biliary excretion amountedto 25% of the mura, Jup. J. Surg. 1972,2, 62) prompted this thor- dosewithin 24 hr, but as faecalexcretionof radipactiough study of the absorption,metabolismand excre- vity in non-cannulatedanimalswas low, it appears tion of d-limonenein rats and its metabolic fate in that biliary metaboliteswere reabsorbedprior to elithe rabbit. mination.The major biliary metabolitewas identified In both studies,the animalsweregiven 14C-labelled as 8-hydroxy-p-menth-1-en-9-yl-P-D-glucopyranosidd-limoneneorally by stomachtube, in a singledose uranic acid, and the effect of this compoundon the of the order of 800mg/kg, and a number of urinary solubilizationof cholesterolgallstonesis under invesmetaboliteswere isolatedand identified. In both rat tigation. and rabbit urine, perillic acid, p-menth-l-ene-$Pdiol, 2870.The metabolismof d-limonene
ANTIOXIDANTS
2871.Propyl gallate:A clandestinesensitizer? Kahn, G., Phanuphak,P. & Claman,H. N. (1974). Propyl gallate-contact sensitization and orally-inducedtolerance.Archs Derm. 109, 506. Propyl gallate (PG) is extensively used as an antioxidant in fats to prevent the developmentof rancidity. It appearsthat no reportsof contact sensitization to PG have appearedin the USA despiteits use there since1947,but evidenceis presentedthat induced immunologicaltolerance may explain this absenceof overt reactions. Ten adult subjectsapplied20%PG in 70%ethanol to the skin of the forearmdaily for 24 days,or until rednessor itching occurred. No subject.developed signsof reaction during the first 14 days but during
wk 3 and 4 five participantscomplainedof pruritus and erythema. These effects were minimal in three casesand subsidedwithin a few days, while in the other two the rash spread to the upper arm neck and trunk within 34 days despite avoidance of further exposureto PG. Two of the mildly sensitized reactors.and 25 non-sensitizedcontrols were then treatedwith 2% PG and 2% lauryl gallatepatch tests for 48 hr. Both sensitizedpersonshad mild positive reactionsto both esterswhile the controls showed no response. In further tests,in guinea-pigs,intradermal injections of @l ml of 5% PG in Freund adjuvant given threetimeson alternatedaysconferredstrongsensitization lasting at least 3 months.The animalscrossreactedto lauryl gallate(weakly) but not to pyrogal101,gaIlic acid or methyl gallate. Three paintings of