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free-radical interactions
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Information section--Fd Chem. Toxic. Vol. 21, no. 5 C A R O T E N O I D / F R E E - R A D I C A L INTERACTIONS
There is some evidence that an increased intake of dietary retinoids and/or carotenoids may protect against the onset of cancer (Cited in F.C.T. 1982, 20, 333; Peto et al. Nature, Lond. 1981, 290, 201). With respect to the carotenoids, such action could be mediated either by retinoid-like activity of certain carotenoids or their derivatives on the control of cellular differentiation in the target tissue or by mechanisms unrelated to cellular differentiation, such as the enhancement of immunological function or the quenching of singlet oxygen (Peto et al. loc. cit.). Singlet oxygen may be generated as a toxic byproduct of normal metabolic processes and is a highly reactive molecular species. It can initiate a chain reaction leading to extensive lipid peroxidation. Foote & Denny (J. Am. chem. Soc. 1968, 90, 6233) demonstrated the ability of carotenoid pigments to quench singlet oxygen generated photochemically. Using a liposome model system, Krinsky & Deneke (J. natn. Cancer Inst. 1982, 69, 205) have investigated the ability of carotenoids to inhibit lipid peroxidation induced not only by singlet oxygen but also by other free radicals. Prepared liposomes, containing trapped glucose, were used in all of the experiments. The extent of lipid peroxidation was determined by measurement of the appearance of malondialdehyde (MDA), a breakdown product of lipid peroxides, and liposome lysis was determined by enzymatic measurement of released glucose. To investigate dye-sensitized photo-oxidations the liposomes were suspended in solutions of toluidine blue and irradiated at wavelengths > 530 nm. The incorporation of /3-carotene or canthaxanthin (4,4'-diketo-fl-carotene) into the liposome membranes greatly reduced liposome lysis induced by dye-sensitized photo-oxidation. When liposomal preparations were incubated with tetraperoxochromate, which is known to generate singlet oxygen and other oxyradical species (superoxide and hy-
droxyl radicals), the rate of lipid peroxidation was considerably decreased in those liposomes prepared with fl-carotene. Ultraviolet (UV) irradiation is known to initiate lipid peroxidation. During UV irradiation, the presence of canthaxanthin in the liposomes considerably delayed the appearance of MDA, and the appearance of M D A coincided with the disappearance of canthaxanthin. M D A formation was also reduced in fl-carotene- or canthaxanthin-containing liposomes in lipid peroxidations accelerated by ferrous ion. The incorporation into liposomes of synthetic phosphatidylcholine containing only saturated fatty acids, rather than egg phosphatidylcholine, prevented the appearance of MDA during UV irradiation. However, /3-carotene bleaching still occurred in this system, indicating that bleaching resulted either from direct interaction of/3-carotene with the triplet sensitizer or from chemical quenching of singlet oxygen. The authors suggest that the ability of carotenoids to inhibit membrane-lipid oxidations initiated by singlet oxygen and other mechanisms may be due to their quenching of free radicals or to their acting as competitive substrates for radical-induced oxidations, thus delaying lipid peroxidation. It has been suggested that anticancer effects may be produced by quenching singlet oxygen, by trapping certain organic free radicals, or by otherwise preventing the lipid peroxidation or other oxidative damage that these chemical species may cause (Peto et al. loc. cit.). The latter authors also noted that the possibility of any role for carotenoids in such effects would depend on determining whether at physiological concentrations these compounds can reduce cellular damage caused by free radicals or unquenched lipid peroxidation, and whether such damage is an important factor in carcinogenesis.
POLYETHYLENE GLYCOL: A FLY IN THE OINTMENT? The polyethylene glycols (PEGs; mixtures of polymers of different molecular weights) have been used as water-soluble bases for medical ointment and cosmetics, and their percutaneous, oral and parenteral toxicities have been considered to be low (Rowe & Wolf in Patty's Industrial Hygiene and Toxicology (Vol. 2C, pp. 3846 3850), edited by G. D. Clayton & F. E. Clayton; John Wiley & Sons, 1982). However, a recent report has implicated a PEG-based antimicrobial cream in the deaths of burn patients whose wounds were treated with the dressing (Sturgill et al. Lab. Invest. 1982, 46, 81A). The report notes that nine out of the ten fatalities were associated with a syndrome of renal failure, metabolic acidosis and elevated anion and osmolality gaps, suggestive of an exogenous toxin. PEG and its metabolites were demonstrated in the serum, while autopsy of six cases showed severe kidney lesions not found in compara-
ble burn patients who were not treated with PEGbased cream. A rabbit model developed to simulate the dressing changes of burn patients (Herold et al. Toxic. appl. Pharmac. 1982, 65, 329) was therefore used to assess the potential toxicity of PEG and of an antimicrobial cream consisting of 0.2~o nitrofurazone in a PEG vehicle (Furacin soluble dressing; FSD). Open skin wounds prepared on New Zealand white rabbits by an aseptic surgical technique were dressed with 20 g FSD or its PEG base (Solu-Base, a blend of three PEG fractions of different average molecular weights but with a preponderance (63~) of a low molecular weight (300) fraction). Controls received no topical medication on their wounds, although all animals were wrapped in sterile gauze. All dressings were changed every 12 hr, with repeated application of the appropriate cream in the case of the test animals. Seven of the eight FSD-treated animals and
Information section--Fd Chem. Toxic. Vol. 21, no. 5 C A R O T E N O I D / F R E E - R A D I C A L INTERACTIONS
There is some evidence that an increased intake of dietary retinoids and/or carotenoids may protect against the onset of cancer (Cited in F.C.T. 1982, 20, 333; Peto et al. Nature, Lond. 1981, 290, 201). With respect to the carotenoids, such action could be mediated either by retinoid-like activity of certain carotenoids or their derivatives on the control of cellular differentiation in the target tissue or by mechanisms unrelated to cellular differentiation, such as the enhancement of immunological function or the quenching of singlet oxygen (Peto et al. loc. cit.). Singlet oxygen may be generated as a toxic byproduct of normal metabolic processes and is a highly reactive molecular species. It can initiate a chain reaction leading to extensive lipid peroxidation. Foote & Denny (J. Am. chem. Soc. 1968, 90, 6233) demonstrated the ability of carotenoid pigments to quench singlet oxygen generated photochemically. Using a liposome model system, Krinsky & Deneke (J. natn. Cancer Inst. 1982, 69, 205) have investigated the ability of carotenoids to inhibit lipid peroxidation induced not only by singlet oxygen but also by other free radicals. Prepared liposomes, containing trapped glucose, were used in all of the experiments. The extent of lipid peroxidation was determined by measurement of the appearance of malondialdehyde (MDA), a breakdown product of lipid peroxides, and liposome lysis was determined by enzymatic measurement of released glucose. To investigate dye-sensitized photo-oxidations the liposomes were suspended in solutions of toluidine blue and irradiated at wavelengths > 530 nm. The incorporation of /3-carotene or canthaxanthin (4,4'-diketo-fl-carotene) into the liposome membranes greatly reduced liposome lysis induced by dye-sensitized photo-oxidation. When liposomal preparations were incubated with tetraperoxochromate, which is known to generate singlet oxygen and other oxyradical species (superoxide and hy-
droxyl radicals), the rate of lipid peroxidation was considerably decreased in those liposomes prepared with fl-carotene. Ultraviolet (UV) irradiation is known to initiate lipid peroxidation. During UV irradiation, the presence of canthaxanthin in the liposomes considerably delayed the appearance of MDA, and the appearance of M D A coincided with the disappearance of canthaxanthin. M D A formation was also reduced in fl-carotene- or canthaxanthin-containing liposomes in lipid peroxidations accelerated by ferrous ion. The incorporation into liposomes of synthetic phosphatidylcholine containing only saturated fatty acids, rather than egg phosphatidylcholine, prevented the appearance of MDA during UV irradiation. However, /3-carotene bleaching still occurred in this system, indicating that bleaching resulted either from direct interaction of/3-carotene with the triplet sensitizer or from chemical quenching of singlet oxygen. The authors suggest that the ability of carotenoids to inhibit membrane-lipid oxidations initiated by singlet oxygen and other mechanisms may be due to their quenching of free radicals or to their acting as competitive substrates for radical-induced oxidations, thus delaying lipid peroxidation. It has been suggested that anticancer effects may be produced by quenching singlet oxygen, by trapping certain organic free radicals, or by otherwise preventing the lipid peroxidation or other oxidative damage that these chemical species may cause (Peto et al. loc. cit.). The latter authors also noted that the possibility of any role for carotenoids in such effects would depend on determining whether at physiological concentrations these compounds can reduce cellular damage caused by free radicals or unquenched lipid peroxidation, and whether such damage is an important factor in carcinogenesis.
POLYETHYLENE GLYCOL: A FLY IN THE OINTMENT? The polyethylene glycols (PEGs; mixtures of polymers of different molecular weights) have been used as water-soluble bases for medical ointment and cosmetics, and their percutaneous, oral and parenteral toxicities have been considered to be low (Rowe & Wolf in Patty's Industrial Hygiene and Toxicology (Vol. 2C, pp. 3846 3850), edited by G. D. Clayton & F. E. Clayton; John Wiley & Sons, 1982). However, a recent report has implicated a PEG-based antimicrobial cream in the deaths of burn patients whose wounds were treated with the dressing (Sturgill et al. Lab. Invest. 1982, 46, 81A). The report notes that nine out of the ten fatalities were associated with a syndrome of renal failure, metabolic acidosis and elevated anion and osmolality gaps, suggestive of an exogenous toxin. PEG and its metabolites were demonstrated in the serum, while autopsy of six cases showed severe kidney lesions not found in compara-
ble burn patients who were not treated with PEGbased cream. A rabbit model developed to simulate the dressing changes of burn patients (Herold et al. Toxic. appl. Pharmac. 1982, 65, 329) was therefore used to assess the potential toxicity of PEG and of an antimicrobial cream consisting of 0.2~o nitrofurazone in a PEG vehicle (Furacin soluble dressing; FSD). Open skin wounds prepared on New Zealand white rabbits by an aseptic surgical technique were dressed with 20 g FSD or its PEG base (Solu-Base, a blend of three PEG fractions of different average molecular weights but with a preponderance (63~) of a low molecular weight (300) fraction). Controls received no topical medication on their wounds, although all animals were wrapped in sterile gauze. All dressings were changed every 12 hr, with repeated application of the appropriate cream in the case of the test animals. Seven of the eight FSD-treated animals and