Chemical research in toxicology
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Chem. Res. Toxicol. · Oct 1999
Effects of mannitol or catalase on the generation of reactive oxygen species leading to DNA damage by Chromium(VI) reduction with ascorbate.
Interaction of Cr(VI) and ascorbate in vitro generates Cr(V), Cr(IV), Cr(III), carbon-based alkyl radicals, COO(*)(-), (*)OH, and ascorbate radicals and induces DNA interstrand cross-links at guanines. To determine which specific Cr species and free radicals cause DNA damage, we investigated the effects of mannitol and catalase on the formation of reactive intermediates, Cr-DNA associations, DNA polymerase-stop sites, and 8-hydroxydeoxyguanosine (8-OHdG) adducts induced by Cr(VI)/ascorbate in a Hepes buffer. EPR spectra showed that mannitol trapped reactive Cr(V), forming a stable Cr(V)-diol complex, and inhibited the radicals induced by Cr(VI)/ascorbate, whereas catalase or heat-denatured catalase enhanced the levels of Cr(V) without altering the radical signals. ⋯ Alternatively, Cr-peroxide intermediates may also lead to 8-OHdG formation to account for the incomplete prevention by mannitol. Catalase or heat-denatured catalase partially protected the formation of 8-OHdG adducts induced by Cr(VI)/ascorbate, suggesting an effect of proteins. Together, the results from this study suggest that the primary species generated during the reduction of Cr(VI) by ascorbate are hydroxyl radicals and Cr(V) species, responsible for the formation of 8-OHdG and DNA cross-links, respectively.
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Chem. Res. Toxicol. · Oct 1996
Human cytochrome P450 2E1 is a major autoantigen associated with halothane hepatitis.
Autoantibodies against specific human cytochrome P450s have been found in the sera of patients suffering from a variety of diseases, including those caused by drugs. In the cases of tienilic acid- and dihydralazine-induced hepatitis, patients have serum autoantibodies directed against cytochromes P450 2C9 and P450 1A2, respectively. ⋯ In addition, because cytochrome P450 2E1 became trifluoroacetylated when it oxidatively metabolized halothane, it is possible that the covalently altered form of cytochrome P450 2E1 may be able to bypass the immunologic tolerance that normally exists against cytochrome P450 2E1. A similar mechanism may explain the formation of autoantibodies that have been found against other cellular targets of the reactive trifluoroacetyl chloride metabolite of halothane.
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Chem. Res. Toxicol. · Mar 1996
Comparative StudyInduction of terata in hamsters by solanidane alkaloids derived from Solanum tuberosum.
The potential induction of terata by solanidanes has been of public health concern since a report in 1972 hypothesized that certain birth defects in humans could be attributed to ingestion of blighted potatoes. The potential teratogenicity of solanidane alkaloids from potatoes and tomatoes in domestic livestock had been considered even earlier. In the present report, oral administration of the steroidal alkaloid glycosides alpha-solanine and alpha-chaconine and their aglycone solanidine is shown to induce craniofacial malformations (exencephaly, encephalocele, and anophthalmia) in Syrian hamsters. ⋯ The teratogenicity of solanidine N-oxide, a putative metabolite, suggests that N-oxidation is not an effective mammalian detoxification pathway. Relative teratogenic potencies (RTP) were assigned to solanidanes by conversion of literature data to equimolar doses compared to the powerful Veratrum teratogen jervine and the nonteratogenic spirosolane tomatidine. RTP values are as follows: jervine (100), 22(S),-25(R)-solanidanes (50), alpha-chaconine (43), alpha-solanine (32), 22(R),25(S)-solanidine (32), solanidine N-oxide (32), 5 alpha,6-dihydrosolanidine (9), and tomatidine (0).