PMID- 19553623
OWN - NLM
STAT- MEDLINE
DCOM- 20091204
LR  - 20211020
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Print)
IS  - 0146-0404 (Linking)
VI  - 50
IP  - 11
DP  - 2009 Nov
TI  - Limited roles of Rdh8, Rdh12, and Abca4 in all-trans-retinal clearance in mouse 
      retina.
PG  - 5435-43
LID - 10.1167/iovs.09-3944 [doi]
AB  - PURPOSE: Although the retinoid cycle is essential for vision, all-trans-retinal 
      and the side products of this cycle are toxic. Delayed clearance of 
      all-trans-retinal causes accumulation of its condensation products, A2E, and 
      all-trans-retinal dimer (RALdi), both associated with human macular degeneration. 
      The protective roles were examined of the all-trans-RDHs, Rdh8 and Rdh12, and the 
      ATP-binding cassette transporter Abca4, retinoid cycle enzymes involved in 
      all-trans-retinal clearance. METHODS: Mice genetically engineered to lack Rdh8, 
      Rdh12, and Abca4, either singly or in various combinations, were investigated 
      because all-trans-retinal clearance is achieved by all-trans-RDHs and Abca4. 
      Knockout mice were evaluated by spectral-domain optical coherence tomography 
      (SD-OCT), electroretinography, retinal morphology, and visual retinoid profiling 
      with HPLC and MS. ARPE19 cells were examined to evaluate A2E and RALdi oxidation 
      and toxicity induced by exposure to UV and blue light. RESULTS: 
      Rdh8(-/-)Abca4(-/-) and Rdh8(-/-)Rdh12(-/-)Abca4(-/-) mice displayed slowly 
      progressive, severe retinal degeneration under room light conditions. Intense 
      light-induced acute retinal degeneration was detected by SD-OCT in 
      Rdh8(-/-)Rdh12(-/-)Abca4(-/-) mice. Amounts of A2E in the RPE correlated with 
      diminished all-trans-retinal clearance, and the highest A2E amounts were found in 
      Rdh8(-/-)Rdh12(-/-)Abca4(-/-) mice. However oxidized A2E was not found in any of 
      these mice, and A2E oxidation was not induced by blue light and UV illumination 
      of A2E-loaded ARPE19 cells. Of interest, addition of all-trans-retinal did 
      activate retinoic acid receptors in cultured cells. CONCLUSIONS: Rdh8, Rdh12, and 
      Abca4 all protect the retina and reduce A2E production by facilitating 
      all-trans-retinal clearance. Delayed all-trans-retinal clearance contributes more 
      than A2E oxidation to light-induced cellular toxicity.
FAU - Maeda, Akiko
AU  - Maeda A
AD  - Department of Pharmacology, , School of Medicine, Case Western Reserve 
      University, 10900 Euclid Avenue, Cleveland, OH 44106-4965, USA. aam19@case.edu
FAU - Golczak, Marcin
AU  - Golczak M
FAU - Maeda, Tadao
AU  - Maeda T
FAU - Palczewski, Krzysztof
AU  - Palczewski K
LA  - eng
GR  - K08 EY019031/EY/NEI NIH HHS/United States
GR  - P30 EY011373/EY/NEI NIH HHS/United States
GR  - EY08123/EY/NEI NIH HHS/United States
GR  - P30EY11373/EY/NEI NIH HHS/United States
GR  - K08EY019031/EY/NEI NIH HHS/United States
GR  - EY09339/EY/NEI NIH HHS/United States
GR  - P30 EY011373-139005/EY/NEI NIH HHS/United States
GR  - R01 EY009339/EY/NEI NIH HHS/United States
GR  - R01 EY009339-20S1/EY/NEI NIH HHS/United States
GR  - R01 EY008123/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20090624
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 0 (A2-E (N-retinylidene-N-retinylethanolamine))
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Abca4 protein, mouse)
RN  - 0 (Pyridinium Compounds)
RN  - 0 (Retinoids)
RN  - EC 1.1.- (Alcohol Oxidoreductases)
RN  - EC 1.1.- (Rdh12 protein, mouse)
RN  - EC 1.1.1.105 (Rdh8 protein, mouse)
RN  - EC 1.2.1.36 (Retinal Dehydrogenase)
RN  - RR725D715M (Retinaldehyde)
SB  - IM
MH  - ATP-Binding Cassette Transporters/*physiology
MH  - Alcohol Oxidoreductases/*physiology
MH  - Animals
MH  - Chromatography, High Pressure Liquid
MH  - Electroretinography
MH  - Humans
MH  - Light/adverse effects
MH  - Mass Spectrometry
MH  - Mice
MH  - Mice, Knockout
MH  - Pyridinium Compounds/metabolism
MH  - Radiation Injuries, Experimental/etiology/*metabolism
MH  - Retina/radiation effects
MH  - Retinal Degeneration/diagnosis/etiology/*metabolism
MH  - Retinal Dehydrogenase/*physiology
MH  - Retinal Pigment Epithelium/metabolism
MH  - Retinaldehyde/*metabolism
MH  - Retinoids/metabolism
MH  - Tomography, Optical Coherence
PMC - PMC2792889
MID - NIHMS161139
COIS- Disclosure: A. Maeda, None; M. Golczak, None; T. Maeda, None; K. Palczewski, None
EDAT- 2009/06/26 09:00
MHDA- 2009/12/16 06:00
PMCR- 2009/12/14
CRDT- 2009/06/26 09:00
PHST- 2009/06/26 09:00 [entrez]
PHST- 2009/06/26 09:00 [pubmed]
PHST- 2009/12/16 06:00 [medline]
PHST- 2009/12/14 00:00 [pmc-release]
AID - iovs.09-3944 [pii]
AID - 10.1167/iovs.09-3944 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2009 Nov;50(11):5435-43. doi: 10.1167/iovs.09-3944. 
      Epub 2009 Jun 24.