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Skin reactions among the lilies
584
Natural products
hepatic lesion is produced in the mid-zonal region. The location of the lesion can be varied by appropriate alteration of the levels of microsomal mixed-function oxidases. Stimulation of these oxidases by phenobarbitone shifts the lesion to a periportal location while their depression by pretreatment with SKF 525A transfers the lesion to the centrilobular area. These' facts suggest that metabolic conversion to an active intermediate probably accounts for the toxic properties of ngaione, but they give no clue to the part of the molecule involved. There are indications, however, from studies of a group of related furan derivatives that produce the same type of liver lesion in mice, that the furan ring with a substituent side chain at position 3 may be important, Preliminary studies showed that simple analogues such as 3-hydroxymethylfuran, 3-carboxyfuran and the methyl ester of the latter produced centrilobular necrosis in mice when given ip at the LDso level (150 380 mg/kg). The site of the necrosis could not be shifted by altering the level of mixed-function oxidase activity. The N-ethylcarbamate derivative of 3-hydroxymethylfuran (with an LDso ofonly 32 mg/kg in mice) produced severe extrahepatic lesions, notably pulmonary oedema and renal tubular necrosis, while hepatic involvement was slight or absent. After the activity of mixed-function oxidases had been increased by phenobarbitone pretreatment, mice could tolerate as much as 50--60 mg/kg. Centrilobular liver necrosis was consistently produced at these dose levels, but the extrahepatic lesions were less severe. Depression of the oxidase activity by carbon disulphide pretreatment did not affect liver injury, but lung and renal lesions occurred at higher doses. The N,N-diethylcarbamate of 3-hydroxymethylfuran produced extensive centrilobular necrosis in a dose of 60 mg/kg (the LDso), while higher doses (100 mg/kg) produced more rapid death associated with pulmonary oedema. Stimulation of mixed-function oxidases changed the location of the liver lesion to the periportal zone, but did not reduce the level of toxicity. Depression of these enzymes by carbon disulphide markedly reduced the liver lesion. These findings suggest that the furan ring substituted in position 3 is basically responsible for the hepatotoxic effect exhibited by the series of substituted furans, although the changes produced depend on the side-chain structure. It seems that hepatic microsomal metabolism has a role to play in the mechanism of the hepatotoxicity and possibly also in the development of the extrahepatic lesions produced by these compounds.
2733. Skin reactions among the lilies
Bleumink, E. & Nater, J. P. (1973). Contact dermatitis to garlic; cross-reactivity between garlic, onion and tulip. Arch. dermatol. Forsch. 247, 117. Some time ago we described the case of a man who showed hyperscnsitivity to garlic and onion, with weak reactivity to tulip, the phenomenon being attributed to a heat- and acid-labile hydrophilic allergen (Cited in F.C.T. 1973, 11,520). A more extensive study has now been reported involving the patch testing of 63 patients with ulcera cruris and 168 with contact dermatitis. Of the first group, 11% gave positive reactions to aqueous and/or ethanolic extracts of garlic and to between one and five of the common test allergens in a standard series. Of the second group, 4.2~ gave a positive reaction to garlic extracts. In neither group was any patient who was sensitive to garlic also sensitive to onion extracts, although both types of extract were prepared by a similar method. One of eight
Natural products
585
patients reacting to garlic gave a positive reaction to tulip extract, while one who had previously shown contact dermatitis attributed to tulip failed to react when tested with garlic extracts. Gas chromatography showed that tuliposide-A (the glucose ester of ~t-methylene-),butyrolactone), the allergenic component of tulip bulbs, was absent from extracts of garlic and onion, so that the possibility of cross-reactivity due to this factor was excluded. Garlic extracts contained tuliposide-B (the glucose ester of :t-methylene-/3-hydroxy-?-butyrolactone), a compound which readily reacts with thiol groups (e.g. in cysteine), but since incubation of garlic with cysteine did not reduce skin reactivity, this compound was unlikely to be involved in epicutaneous reactions to garlic. The active compound in garlic allergy was concluded to be a low-molecular-weight, hydrophilic, heat- and acid-labile substance, which could be expected to be inactivated during normal cooking processes. Many persons who reacted to garlic reacted positively to some or all of the common allergens, coal tar, wood tar, Peruvian balsam, wool alcohols and colophony, and the presence of some cross-reacting substance common to these materials cannot bc ruled out.
2734. Gossypol locks up the iron Herman, D. L. & Smith, F. H. (1973). Effect of bound gossypol on the absorption of iron by rats. J. Nutr. 103, 882. It has becn reported that diets containing 10% cottonseed protein containing bound gossypol at levels up to 0681~/ohad little effect on the growth of weanling rats, but higher concentrations of bound gossypol impaired weight gain, probably by reducing the availability of essential amino acids (Cited in F.C.T. 1973, I 1,695). The toxic effects of gossypol have been reduced or eliminated by the addition of divalent iron to the diet of nonruminant animals, and the finding that iron would form a complex with gossypol in vitro prompted an investigation into the importance of this reaction in the gastro-intestinal tract. In rats fed 0.005 (control), 0.12, 0-24 or 0"35~o bound gossypol in the diet, the absorption of divalent iron. added to the feed at levels of 400 and 1600 ppm, decreased linearly with increasing gossypol concentration. When dietary iron (as ferrous sulphate) was increased, the absolute quantity of iron absorbed increased, although there was a reduction in absorption expressed as a proportion of the total ingested. The levels of free and bound gossypol in the animals' livers rose as the feed content was increased, but diminished with any increase in iron intake. It is suggested that if a gossypol-iron complex is formed in the liver rather than in the gut, biliary excretion of this complex and its consequent loss in the faeces could explain the apparent reduction in iron absorption in gossypol-fed rats. This study indicates, however, that bound gossypol in thc diet complexes with iron in the intestinal tract with a consequent reduction in the absorption of both components.
2735. Tannic acid and vitamin Bt2 absorption Carrera, G., Mitjavila, S. et Derache, R. (1973). Influence de l'acide tannique sur la disponibilit6 digestive de la vitamine B12 chez le rat. Ann. Nutr. Alim. 27, 73. I(T
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Natural products
hepatic lesion is produced in the mid-zonal region. The location of the lesion can be varied by appropriate alteration of the levels of microsomal mixed-function oxidases. Stimulation of these oxidases by phenobarbitone shifts the lesion to a periportal location while their depression by pretreatment with SKF 525A transfers the lesion to the centrilobular area. These' facts suggest that metabolic conversion to an active intermediate probably accounts for the toxic properties of ngaione, but they give no clue to the part of the molecule involved. There are indications, however, from studies of a group of related furan derivatives that produce the same type of liver lesion in mice, that the furan ring with a substituent side chain at position 3 may be important, Preliminary studies showed that simple analogues such as 3-hydroxymethylfuran, 3-carboxyfuran and the methyl ester of the latter produced centrilobular necrosis in mice when given ip at the LDso level (150 380 mg/kg). The site of the necrosis could not be shifted by altering the level of mixed-function oxidase activity. The N-ethylcarbamate derivative of 3-hydroxymethylfuran (with an LDso ofonly 32 mg/kg in mice) produced severe extrahepatic lesions, notably pulmonary oedema and renal tubular necrosis, while hepatic involvement was slight or absent. After the activity of mixed-function oxidases had been increased by phenobarbitone pretreatment, mice could tolerate as much as 50--60 mg/kg. Centrilobular liver necrosis was consistently produced at these dose levels, but the extrahepatic lesions were less severe. Depression of the oxidase activity by carbon disulphide pretreatment did not affect liver injury, but lung and renal lesions occurred at higher doses. The N,N-diethylcarbamate of 3-hydroxymethylfuran produced extensive centrilobular necrosis in a dose of 60 mg/kg (the LDso), while higher doses (100 mg/kg) produced more rapid death associated with pulmonary oedema. Stimulation of mixed-function oxidases changed the location of the liver lesion to the periportal zone, but did not reduce the level of toxicity. Depression of these enzymes by carbon disulphide markedly reduced the liver lesion. These findings suggest that the furan ring substituted in position 3 is basically responsible for the hepatotoxic effect exhibited by the series of substituted furans, although the changes produced depend on the side-chain structure. It seems that hepatic microsomal metabolism has a role to play in the mechanism of the hepatotoxicity and possibly also in the development of the extrahepatic lesions produced by these compounds.
2733. Skin reactions among the lilies
Bleumink, E. & Nater, J. P. (1973). Contact dermatitis to garlic; cross-reactivity between garlic, onion and tulip. Arch. dermatol. Forsch. 247, 117. Some time ago we described the case of a man who showed hyperscnsitivity to garlic and onion, with weak reactivity to tulip, the phenomenon being attributed to a heat- and acid-labile hydrophilic allergen (Cited in F.C.T. 1973, 11,520). A more extensive study has now been reported involving the patch testing of 63 patients with ulcera cruris and 168 with contact dermatitis. Of the first group, 11% gave positive reactions to aqueous and/or ethanolic extracts of garlic and to between one and five of the common test allergens in a standard series. Of the second group, 4.2~ gave a positive reaction to garlic extracts. In neither group was any patient who was sensitive to garlic also sensitive to onion extracts, although both types of extract were prepared by a similar method. One of eight
Natural products
585
patients reacting to garlic gave a positive reaction to tulip extract, while one who had previously shown contact dermatitis attributed to tulip failed to react when tested with garlic extracts. Gas chromatography showed that tuliposide-A (the glucose ester of ~t-methylene-),butyrolactone), the allergenic component of tulip bulbs, was absent from extracts of garlic and onion, so that the possibility of cross-reactivity due to this factor was excluded. Garlic extracts contained tuliposide-B (the glucose ester of :t-methylene-/3-hydroxy-?-butyrolactone), a compound which readily reacts with thiol groups (e.g. in cysteine), but since incubation of garlic with cysteine did not reduce skin reactivity, this compound was unlikely to be involved in epicutaneous reactions to garlic. The active compound in garlic allergy was concluded to be a low-molecular-weight, hydrophilic, heat- and acid-labile substance, which could be expected to be inactivated during normal cooking processes. Many persons who reacted to garlic reacted positively to some or all of the common allergens, coal tar, wood tar, Peruvian balsam, wool alcohols and colophony, and the presence of some cross-reacting substance common to these materials cannot bc ruled out.
2734. Gossypol locks up the iron Herman, D. L. & Smith, F. H. (1973). Effect of bound gossypol on the absorption of iron by rats. J. Nutr. 103, 882. It has becn reported that diets containing 10% cottonseed protein containing bound gossypol at levels up to 0681~/ohad little effect on the growth of weanling rats, but higher concentrations of bound gossypol impaired weight gain, probably by reducing the availability of essential amino acids (Cited in F.C.T. 1973, I 1,695). The toxic effects of gossypol have been reduced or eliminated by the addition of divalent iron to the diet of nonruminant animals, and the finding that iron would form a complex with gossypol in vitro prompted an investigation into the importance of this reaction in the gastro-intestinal tract. In rats fed 0.005 (control), 0.12, 0-24 or 0"35~o bound gossypol in the diet, the absorption of divalent iron. added to the feed at levels of 400 and 1600 ppm, decreased linearly with increasing gossypol concentration. When dietary iron (as ferrous sulphate) was increased, the absolute quantity of iron absorbed increased, although there was a reduction in absorption expressed as a proportion of the total ingested. The levels of free and bound gossypol in the animals' livers rose as the feed content was increased, but diminished with any increase in iron intake. It is suggested that if a gossypol-iron complex is formed in the liver rather than in the gut, biliary excretion of this complex and its consequent loss in the faeces could explain the apparent reduction in iron absorption in gossypol-fed rats. This study indicates, however, that bound gossypol in thc diet complexes with iron in the intestinal tract with a consequent reduction in the absorption of both components.
2735. Tannic acid and vitamin Bt2 absorption Carrera, G., Mitjavila, S. et Derache, R. (1973). Influence de l'acide tannique sur la disponibilit6 digestive de la vitamine B12 chez le rat. Ann. Nutr. Alim. 27, 73. I(T
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