Carotenoid inhibitors

Since GAs as diterpenes share many intermediates in the biosynthetic steps leading to other terpenoids, eg, cytokinins, ABA, sterols, and carotenoids, inhibitors of the mevalonate (MVA) pathway of terpene synthesis also inhibit GA synthesis (57). Biosynthesis of GAs progresses in three stages, ie, formation of / Akaurene from MVA, oxidation of /-kaurene to GA 2" hyde, and further oxidation of the GA22-aldehyde to form the different GAs more than 70 different GAs have been identified. 

Fluridone is a herbicide that is a gamma-pyridone derivative. It is a carotenoid inhibitor this is a well-known type of activity that interferes with the photosynthesis process in such a way as to lead to production of the plant-lethal singlet oxygen. 

Bleaching Herbicides. Membrane-based modes of herbicidal action relevant to photosynthesis (37) include those of inhibitors of carotenoid biosynthesis, eg, norflura2on, diftmon, y -phenoxyben2amines inhibitors of chlorophyll biosynthesis, eg, oxadia2on, DTP or... 

WOLF G (1992) Retinoids and carotenoids as inhibitors of carcinogesesis and inducers of cell-cell communication. Nutr Revs 50(9) 270-74. 

The carotenoid pathway may also be regulated by feedback inhibition from the end products. Inhibition of lycopene cyclisation in leaves of tomato causes increase in the expression of Pds and Psy-1 (Giuliano et al, 1993 Corona et al, 1996). This hypothesis is supported by other studies using carotenoid biosynthesis inhibitors where treated photosynthetic tissues accumulated higher concentrations of carotenoids than untreated tissues (reviewed by Bramley, 1993). The mechanism of this regulation is unknown. A contrary view, however, comes from studies on the phytoene-accumulating immutans mutant of Arabidopsis, where there is no feedback inhibition of phytoene desaturase gene expression (Wetzel and Rodermel, 1998). 

Caco-2 cells and ezetimibe, a potent inhibitor of chloresterol absorption in humans, it was reported that (1) carotenoid transport was inhibited by ezetimibe up to 50% and the extent of that inhibition diminished with increasing polarity of the carotenoid molecule, (2) the inhibitory effects of ezetimibe and the antibody against SR-BI on P-carotene transport were additive, and (3) ezetimibe may interact physically with cholesterol transporters as previously suggested - and also down-regulate the gene expression of three surface receptors, SR-BI, NPCILI, and ABCAl. 

Nucleic acids are not the only biomolecules susceptible to damage by carotenoid degradation products. Degradation products of (3-carotene have been shown to induce damage to mitochondrial proteins and lipids (Siems et al., 2002), to inhibit mitochondrial respiration in isolated rat liver mitochondria, and to induce uncoupling of oxidative phosphorylation (Siems et al., 2005). Moreover, it has been demonstrated that the degradation products of (3-carotene, which include various aldehydes, are more potent inhibitors of Na-K ATPase than 4-hydroxynonenal, an aldehydic product of lipid peroxidaton (Siems et al., 2000). 

The first study was conducted to determine whether carotenoids and cholesterol share common pathways (transporters) for their intestinal absorption (During et al., 2005). Differentiated Caco-2 cells on membranes were incubated (16 h) with a carotenoid (1 pmol/L) with or without ezetimibe (EZ Zetia, an inhibitor of cholesterol transport), and with or without antibodies against the receptors, cluster determinant 36 (CD36) and scavenger receptor class B, type I (SR-BI). Carotenoid transport in Caco-2 cells (cellular uptake + secretion) was decreased by EZ (lOmg/L) as follows P-C and a-C (50% inhibition) P-cryptoxanthin and LYC (20%) LUT ZEA (1 1) (7%). EZ reduced cholesterol transport by 31%, but not retinol transport. P-Carotene transport was also inhibited by anti-SR-BI, but not by anti-CD36. The inhibitory effects of EZ and anti-SR-BI on P-C transport... 

As demonstrated above, the uptake of [1-C at the apical membrane of differentiated Caco-2 cells occurs via a saturable, facilitated mechanism and is inhibited by Ezetimibe, a clinically used inhibitor of cholesterol absorption. Carotenoids secreted at the basolateral membrane were associated... 

In a recent study, the antiproliferative effect of different carotenoids, including (3-carotene, lycopene and lutein, on PCNA and cyclin Dl expression in human KB cells have been studied. The results indicate that carotenoids suppressed cell growth by acting as inhibitors of the expressions of PCNA and cyclin Dl, although in a different extent (Cheng et al., 2007). On the other hand, (3-carotene was able to induce a cell cycle delay in G2/M phase by decreasing the expression of cyclin A in human colon adenocarcinoma cells (Palozza et al., 2002a). 

On the other hand, several ROS are highly cytotoxic. Consequently, eukaryotic cells have developed an elaborate arsenal of antioxidant mechanisms to neutrahze their deleterious effects (enzymes such as superoxide dismutases, catalases, glutathione peroxidases, thioredoxin inhibitors of free-radical chain reaction such as tocopherol, carotenoids, ascorbic acid chelating proteins such as lactoferrin and transferrin). It can be postulated that ROS may induce an oxidative stress leading to cell death when the level of intracellular ROS exceeds an undefined threshold. Indeed, numerous observations have shown that ROS are mediators of cell death, particularly apoptosis (Maziere et al., 2000 Girotti, 1998 Kinscherf et al., 1998 Suzuki et al., 1997 Buttke and Sanstrom, 1994 Albina et al., 1993). 

The molecular target site of triketone herbicides is the enzyme -hydroxyphenylpyruvate dioxygenase (HPPD). Inhibition of this enzyme disrupts the biosynthesis of carotenoids and causes a bleaching (loss of chlorophyll) effect on the foliage similar to that observed with inhibitors ofphytoene desaturase (e.g. norflurazon). However, the mechanism of action of HPPD inhibitors is different. Inhibtion of HPPD stops the synthesis of homogen tisate (HGA), which is a key precursor of the 8 different tocochromanols (tocopherols and tocotrienols) and prenyl quinones. In the absence of prenylquinone plastoquinone, phytoene desaturase activity is interrupted. The bleaching of the green tissues ensues as if these compounds inhibited phytoene desaturase. 

Inhibitors have been used to investigate the biosynthesis of 1,2-dihydroneuro-sporene [l,2,7,8-tetrahydro-i/, i/f-carotene (143)] and related 1,2-dihydro-carotenoids in Rhodopseudomonas viridis, and possible alternative sequences are presented.The C-1,2 hydrogenation reaction is inhibited by CPTA [2-(4-chlorophenylthio)triethylammonium chloride], a compound known to inhibit cyclization and C-1,2-hydration in other systems, thus indicating possible similarity of the reactions involved. 

The cyclization inhibitor nicotine prevents formation of the C50 carotenoid bacterioruberin [2,2 -bis-(3-hydroxy-3-methylbutyl)-3,4,3, 4 -tetradehydro-... 

The pyridazin-3-ones are interesting because they include herbicides having two different modes of action, distinguished only by small changes in substitution pattern. Thus pyrazon (8) (61GEP1105232) is a photosynthesis inhibitor, while other discussed later are carotenoid biosynthesis inhibitors. The pyridazin-3-one ring is constructed by condensation of phenyl-hydrazine with 3,4-dichloro-2,5-dihydro-5-hydroxyfuran-2-one (9), in turn produced by chlorination of furan-2-carbaldehyde. Amination of (10) then occurs exclusively at the 5-position to give pyrazon (Scheme 4). 

Substitution of a trifluoromethyl group in the 3-position of the benzene ring and alkylation of the 4-amino group, as in norflurazon (16) (69FRP1575643), turns the pyridazin-3-ones into inhibitors of carotenoid biosynthesis. A similar substitution pattern occurs in fluridone (17) (74GEP2537753). The long-established l,2,4-triazol-3-ylamine, known as amitrole, and... 

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