Studies on porphyria and heme metabolism caused by environmental chemicals.
| Project/Area Number |
58440039
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| Research Category |
Grant-in-Aid for General Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
公衆衛生学
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| Research Institution | Kyoto University |
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Principal Investigator |
SANO Seiyo 京都大学, 医, 教授 (60025533)
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| Project Period (FY) |
1983 – 1985
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| Project Status |
Completed (Fiscal Year 1985)
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| Budget Amount *help |
¥33,800,000 (Direct Cost: ¥33,800,000)
Fiscal Year 1985: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1984: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1983: ¥29,000,000 (Direct Cost: ¥29,000,000)
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| Keywords | Uroporphyrinogen decarboxylase / Porphyrin / ESR / singlet oxygen / heme / 【^(32)P】-ラベルDNA / 一重項酸 |
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| Research Abstract |
1) Time course of induction of <delta> -aminolevulinic acid (ALA) synthertase, cytochrome P-450 and mixed function oxidase and inhibition of uroporphyrinogen decarboxylase (Uro-gen D) in the liver of C57BL/6 mice and ddY mice fed polychlorinated biphenyl (PCB) was investigated to clarify the role of inhibition of Uro-gen D. Male mice of C57BL/6 fed a diet containing 300 ppm of 3,4,5,3',4',5'-hexachlorobiphenyl or 500 ppm of a commercial PCB for more than 3 weeks accumulated an extremely large amount of uroporphyrin in the liver. The activity of Uro-gen D was depressed about 40% within 1 week and about 80% within 3 weeks. Male mice of ddY showed only a little increase of uroporphyrin accumulation and a moderate decrease of Uro-gen D activity even for the prolonged period (10 weeks). These results indicate that the development of porphyria do not causually relate with induction of drug-metabolizing function, but with inhibition Uro-gen D.
2) Photodynamic modification of DNA by hematoporph
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yrin (Hp) was characterized by the DNA sequencing technique using <^(32)P> -labeled DNA fragments, and the reaction mechanism was investigated by ESR spectroscopy. Mild photodynamic treatment of single-stranded DNA with Hp induced an alteration of guanine residues, and subsequent treatment with piperidine leaded to chain cleavages at each guanine residue. ESR studies demonstrated that photoexcited Hp reacts with oxygen to generate singlet oxygen oxidizing the guanine residues of single-stranded DNA.
3) <alpha> -Oxyprotohemin IX, an early intermediate in heme catabolism, was synthesized and its autoxidation to biliverdin IX <alpha> was studied. In anaerobic aqueous pyridine, <alpha> -oxyprotohemin underwent autoreduction to yield an Fe(II) <alpha> -oxyporphyrin <pi> -neutral radical bis (pyridine) complex, which reacted with an equimolar amount of dioxygen to give pyridineverdohemochrome IX <alpha> and CO via an intermediate. Reconstituted apomyoglobin <alpha> -oxyprotogemin IX complex reacted with dioxygen to form an Fe(II) oxyporphyrin <pi> -neutral radical intermediate, which rearranged to a green compound with elision of CO. The green product, an apomyoglobin verdoheme <pi> -radical complex, reacted with dioxygen to give Fe(III)biliverdin IX <alpha> . Less
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