2000 Fiscal Year Final Research Report Summary
Characterization of retinoic acid synthases
| Project/Area Number |
11670129
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
General medical chemistry
|
|---|
| Research Institution | Kagawa Medical University |
|---|
Principal Investigator |
TOMITA Shuhei Kagawa Medical University, Department of Biochemistry, Assistant Professor, 医学部, 助手 (00263898)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
FURUKAWA Aizo Kagawa Medical University, Department of Biochemistry, Assistant Professor, 医学部, 助手 (80304583)
|
|---|
| Project Period (FY) |
1999 – 2000
|
| Keywords | retinoic acid synthase / oxidoreductase / cytochrome P-450 / CYP1A1 / Retinoic acid / Vitamin A |
|---|
| Research Abstract |
Retinoic acid (RA) is a bio-active small lipid related with cell differentiation and proliferation. The functional activation of RA should be regulated by several steps from its metabolism to phenotypic response in the cell. The RA synthesis is one of the critical step for the RA activation and we have gotten a evidence that CYP1A1 catalyzed RA synthesis from retinal. During this two years, we have investigated the possibility of RA synthesis catalyzed by CYP1A1 in vivo.
New tumor formation was suppressed by RA administration in xeroderma pigmentosum (XP) patients who have a defect in nuclear excision repair. However, the inhibition is not due to enhanced removal of UV-damaged DNA.These results promoted us to investigate whether or not RA metabolism is abnormal in XP fibroblasts and what the underlying mechanism is. Compared with wild type fibroblasts, low activities of RA synthesis were determined on HPLC in mouse fibroblasts lacking XP group A (XPA) gene and UV-induced XPA deficient cancer cells. Moreover, we observed an impaired expression of cytochrome P450 1A1 in XPA deficient fibroblasts by RT-PCR and decreased expression of retinoic acie receptor γ in XPA deficient cancer cells by western blotting. Finally, pretreatment of RA isoforms significantly protected the XPA deficient fibroblasts from UV-induced death. These results suggest that decreased structure activity of RA synthesis, resulting from impaired mRNA expression of cytochrome P450 1A1 may, at least together with UV irradiation, involve in skin carcinogenesis in XP patients.
To investigate the relationship between RA an CYP1A1 with another approach, we recently started analyzing Arylhydrocarbon Receptor (AhR) knockout mice which has more retinoic acid contents in the liver than that of normal mice.
|
