Furanocoumarins linear

Phytoalexins are low molecular weight compounds produced in plants as a defense mechanism against microorganisms. They do, however, exhibit toxicity to humans and other animals in addition to microbes (30). Coumarins, glycoalkaloids, isocoumarins, isoflavonoids, linear furanocoumarins, stilbenes, and terpenes aU. fall into the category of phytoalexins (31). Because phytoalexins are natural components of plants, and because their concentration may increase as a response to production and management stimuli, it is useful to recogni2e the possible effects of phytoalexins in the human diet. 

CYP6D1 of the housefly (Musca domestica) has been found to hydroxylate cyper-methrin and thereby provide a resistance mechanism to this compound and other pyrethroids in this species (Scott et al. 1998 see also Chapter 12). Also, this insect P450 can metabolize plant toxins such as the linear furanocoumarins xanthotoxin and bergapten (Ma et al. 1994). This metabolic capability has been found in the lepi-dopteran Papilio polyxenes (black swallowtail), a species that feeds almost exclusively on plants containing furanocoumarins. 

Ma, R., Cohen, M.B., and Berenbaum, M.R. et al. (1994). Black swallowtail alleles encode cytochrome P450s that selectively metabolise linear furanocoumarins. Archives of Biochemistry and Biophysics 310, 332-340. 

Diawara M M, Trumble J T, Quiros C F and Hansen R (1995), Implications of distributions of linear furanocoumarins within celery , J Agric Food Chem, 43, 723-727. 

Hadacek F, Mueller C, Werner A, Greger H, Proksch P, Analysis, isolation and insecticidal activity of linear furanocoumarins and other coumarin derivatives from Peuxedanum (Apiaceae Apioideae),/ Ecol 20 2035—2054, 1994. 

Because the resistance of polyxenes to the toxic effects of linear furanocoumarins apparently does not extend to the angular furanocoumarins (22), we have undertaken comparative metabolic fate studies with a representative of each of these furanocoumarin classes. Tritlated psoralen or isopsoralen (Figure 1) was administered as before to last stage polyxenes caterpillars, and the distribution, elimination, and biochemical fate of the compounds determined (28). 

Our studies with polyxenes caterpillars and radiolabeled furanocoumarins have provided what appears to be a definitive explanation of the apparent total Insensitivity of these insects to the toxic effects of linear furanocoumarins present in their... 

Figure 1. Structures of a linear furanocoumarin (psoralen) and an angular furanocoumarin (isopsoralen).

Our studies indicate that rapid metabolic detoxification of linear furanocoumarins is an effective resistance mechanism for K polyxenes against the toxic effects of these compounds. It has been postulated that the adaptation of some plants to produce angular furanocoumarins was in response to the reduced effectiveness of the linear furanocoumarins as deterrents for herbivores such as polyxenes (22). Such may Indeed be true, but our studies on the comparative detoxification of linear and angular furanocoumarins suggest that, at best, the presence of angular furanocoumarins in plants confers only a tenuous margin of relative "safety" against polyxenes. 

Linear furanocoumarins (psoralens) inhibit P450s as mechanism-based inactivators (suicide inhibitors). Thus, species that produce psoralens may have evolved C4H enzymes with enhanced tolerance to these compounds. Recombinant C4H from the psoralen-producing species R. graveolens showed markedly slower inhibition kinetics with psoralens, and possibly biologically significant tolerance, compared to C4H from a species that does not produce the compounds (H. tuberosus) ... 

Linear furanocoumarins are polenl photosensitizing agents in celery, parsley, parsnips, limes, and figs. The most commonly reported symptoms include contact dermatitis and photodermatitis. particularly on the hands and forearms. 

Beier, R.C., Ivie, G.W. and Oertli, E.H. (1 994) Linear furanocoumarins and graveolone from the common herb parsley. Phytochemistry 36(4), 869-872. 

The enzyme that catalyses the conversion of DMAPP and umbelliferone into 6-dimethylallylumbelliferone, the first reaction specifically directed to the biosynthesis of linear furanocoumarins, has been isolated394 from suspension cultures and young leaves of Ruta graveolens. The particulate enzyme could utilize neither herniarin as a substitute for umbelliferone nor GPP in place of DMAPP. 8-Dimethylallylumbelliferone, which is an intermediate in the formation of the angular furanocoumarins, was not formed by these preparations. 

Bull, D.L., Ivie, G.W., Beier, R.C., and Pryor, N.W., In vitro metabolism of a linear furanocoumarin (8-methoxypsoralen, xanthotoxin) by mixed-function oxidases of larvae of black swallowtail butterfly and fall army worm, /. Chem. Ecol., 12,885,1986. 

Figure 4.3 Structures of coumarins, linear furanocoumarins and angular furanocoumarins.

Ysyn and para (8) effects of alkyl and O-alkyl substituents in linear furanocoumarins can be used to distinguish between the substituent s position, C-5 or C-8 (77). Moreover, such effects of substituents at C-5 allow a differentiation between linear and angular furanocoumarins (77). 

Other classes of compounds that inactivate human and rat liver microsomal P450 enzymes via protein modification are known. One such class is represented by the fiiranocoumarins, natural constituents of foods such as celery, parsley, figs, parsnips, and grapefruit juice . Among these compormds, the photoactive linear furanocoumarin, 8-MOP (methoxsalen) is a particularly potent P450 inactivator. Evidence that... 

It has been shown that in insects cytochrome P450 monooxygenases are involved in metabolism of host plant allelochemicals by Lepidoptera larvae. Expression of the CYP6B1 alleles in lepidopteran cell lines has demonstrated that both P450 isoforms metabolize substantial amounts of linear furanocoumarins, such as xanthotoxin and bergapten, but not angular furanocoumarins, such as angelicin (4) and sphondin [249]. 

The furanocoumarins, psoralen, bergapten, xanthotoxin and isopimpinellin, were detected in celery leaves and stalk. The total furanocoumarin content ranged from about 12 to 50 mg/kg in Florida cultivars [54]. Treatment with fungicides increased the bergapten content 2-4 times in leaves and stalk, xanthotoxin 2-3 times in stalk, and isopimpinellin about 2-3 times in leaves, while psoralen levels remained constant. This fact is of some importance since linear furanocoumarins are the cause of photosensitive reactions in humans. 

Psoralens. Many plants contain linear furanocoumarins... 

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