Retinoids cleavage

Interestingly, carotenoids more abundant in the blood plasma than zeaxanthin, such as lycopene, P-carotene, and P-cryptoxanthin, do not accumulate in the retina. RPE cells express p,p-carotene 15,15 -monooxygenase (BCO), formerly known as P-carotene 15,l5 -dioxygcnase, an enzyme that catalyzes the oxidative cleavage of P-carotene into two molecules of all-trans-retinal (Aleman et al., 2001 Bhatti et al., 2003 Chichili et al., 2005 Leuenberger et al., 2001 Lindqvist and Andersson, 2002). Therefore it may be suggested that p -carotene transported into RPE-cells is efficiently cleaved into retinal molecules. BCO cleaves also P-cryptoxanthin (Lindqvist and Andersson, 2002), and its absence in the retina may also be explained by its efficient cleavage to retinoids. However, lycopene, often the most abundant carotenoid in human plasma, cannot serve as a substrate for BCO, and yet it is not detectable in the neural retina (Khachik et al., 2002). 

Numerous studies have demonstrated that degradation products of (3-carotene exhibit deleterious effects in cellular systems (Alija et al., 2004, 2006 Hurst et al., 2005 Salerno et al., 2005 Siems et al., 2003). A mixture of (3-carotene degradation products exerts pro-apoptotic effects and cytotoxicity to human neutrophils (Salerno et al., 2005 Siems et al., 2003), and enhances the geno-toxic effects of oxidative stress in primary rat hepatocytes (Alija et al., 2004, 2006), as well as dramatically reduces mitochondrial activity in a human leukaemic cell line, K562, and RPE 28 SV4 cell line derived from stably transformed fetal human retinal pigmented epithelial cells (Hurst et al., 2005). As a result of degradation or enzymatic cleavage of (3-carotene, retinoids are formed, which are powerful modulators of cell proliferation, differentiation, and apoptosis (Blomhoff and Blomhoff, 2006). 

Pro-vitamin A cleavage and formation of retinoids via eccentric and central cleavage of p,p... 

Ziouzenkova, O., G. Orasanu, G. Sukhova et al. 2007b. Asymmetric cleavage of beta-carotene yields a transcriptional repressor of retinoid X receptor and peroxisome proliferator-activated receptor responses. Mol Endocrinol 21( 1) 77—88. 

The central cleavage of P-carotene 1 is most likely the major pathway by which mammals produce the required retinoids il), in particular, retinal 2, which is essential for vision and is subsequently oxidized to retinoic acid 3 and reduced to retinol 4. An alternative excentric cleavage of 1 has been reported involving scission of the double bond at C7-C8 producing P-8 -apocarotenal 5 (2a,2b) which is subsequently oxidized to 2 (Fig. 1) (2c). The significance of carotene metabolites such as 2, 3 and 4 to embryonic development and other vital processes such as skin and membrane protection is a major concern of medicinal chemistry. 

Vitamin A (retinol) is the parent substance of the retinoids, which include retinal and retinoic acid. The retinoids also can be synthesized by cleavage from the provitamin (3-car-otene. Retinoids are found in meat-containing diets, whereas p-carotene occurs in fruits and vegetables (particularly carrots). Retinal is involved in visual processes as the pigment of... 

The P-carotene may undergo central or eccentric cleavage with the formation of retinoids, or may be released unchanged into the blood-flow. 

In no instance did the synthetic retinoid possess as great an inhibitory capacity as do retinol or retinyl acetate. In addition, the provitamin g-carotene had no effect on mutagenicity of 2-fluorenamine in Salmonella regardless of the carcinogen activation system (Tables III and IV). Thus, 3-carotene would apparently require enzymatic cleavage to vitamin A in order to have an effect in this ijri vitro bioassay and exerts no role by itself in modulating the metabolism of chemical carcinogens in the model system. 

Abbreviations a-BFAs anteiso-branched fatty acids AGP acyl carrier protein BHLH active soluble domain of SREBP CNS central nervous system DSD delta 5 desaturase D6D delta 6 desaturase ER endoplasmic reticulum Hik histidine kinase HUFA highly unsaturated fatty acid LXR liver X receptor MUFA monounsaturated fatty add NF-Y nuclear factor Y PLs phospholipids PP peroxisome proliferator PPAR PP-activated receptor PPRE PP response element PUFA polyunsaturated fatty acid PUFA-BP PUFA binding protein PUFA-RE PUFA response element RXR retinoid X receptor SCAP SREBP cleavage-activating protein SCD steraroyl CoA desaturase SFA saturated fatty acid SRE sterol response... 

FIGURE 21.3 Structures of P-carotene, zXX-trans retinoic acid, 9-cis retinoic acid, and lycopene. P-Carotene is a provitamin A carotenoid that can undergo central cleavage to form two molecules of retinal. Retinal can undergo further metabolism to form the retinoids, dX -trans retinoic acid and 9-cis retinoic acid, which regulate gene expression via nuclear retinoic acid receptors. Lycopene is a nonprovitamin A carotenoid. 

Kim, Y. K., L. Wassef, S. Chung, et al. 2011. P-Carotene and Its Cleavage Enzyme P-Carotene-15,15 -Oxygenase (Cmol) Affect Retinoid Metabolism in Developing Tissues. Faseb J 25, no 5 1641-52. 

Both RALDHl and RALDH2 also catalyze the conversion of 9-cw-retinal into 9-cis-RA [72, 73]. Therefore, they could also serve as partners with the ci s-retinoid RDH in a pathway that generates 9-cis-RA from 9-cw-retinol. Alternatively, they could catalyze synthesis of 9-cis-RA from 9-cw-retinal produced by central cleavage of 9-cw-p-carotene [74]. 

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