Dietary cancer risk from conditional cancerogens (tumor promoters) in produce of livestock fed on species of spurge ( Euphorbiaceae )

Abstract

Irritant diterpene ester toxins were isolated from Euphorbia nubica and E. helioscopia, which are contaminants of the green fodder of livestock in Egypt. Fractionations of methanol extracts of aerial parts of both plants were monitored by the irritation unit on the mouse ear. Plant extracts were subjected to multiplicative distribution methods, yielding irritant hydrophilic fractions that were further purified by column chromatography. Final purification of the materials was achieved by TLC (silica gel) followed by HPLC, or by TLC alone. In this way, from E. nubica, five Euphorbia factors (Nu1-Nu5) were isolated and characterized as short-chain polyfunctional diterpene esters of tigliane-type parent alcohols. The two weak irritants Nul and Nu3 were triesters of 4-deoxy(4alpha)phorbol. Nu2 was shown to be a triester of the stereoisomeric tigliane-type parent alcohol 4-deoxyphorbol. Weak irritant Nu4 probably is a positional isomer of Nu2. Nu5 was characterized as a short-chain triester of 4,20-dideoxy-5xi-hydroxyphorbol. From E. helioscopia, six short- to medium-chain polyfunctional diterpene esters of the ingenane type, generally containing unsaturated acids were obtained, i.e., four irritant esters of ingenol (Euphorbia factors H1, H2, H5, and H6) and two esters of 20-deoxyingenol (non-irritant Euphorbia substance HS4, and irritant Euphorbia factor H8). All irritant Euphorbia factors of the tigliane and ingenane diterpene ester type described in this investigation are considered to be more or less active tumor promoters, i.e., conditional (non-genotoxic) cancerogens. The Euphorbia factors assayed exhibited moderate (H1) to low (H8) relative tumor-promoting potency in comparison to the ingenane prototype DTE tumor promoter 3-TI.

Tigliane Diterpenoids from the Euphorbiaceae and Thymelaeaceae Families

“…103 A mixture of the 4deoxyphorbol-12,13-diesters (148 and 149) showed high irritant activity, 106 whereas the 12,13,20-triesters of 4deoxyphorbol (157, 170, and 171) exhibited only moderate irritant activities. 109 These results were in agreement with the trends observed for the 12-deoxyphorbol esters, in that the presence of a free hydroxy group at C-20 together with a transfused A/B ring system appeared to be important to the irritant effects of these compounds. Furthermore, the 4-OH was not critical to the irritant activity of these compounds.…”

An Overview of Biotransformation and Toxicity of Diterpenes

“…Diterpenes from Euphorbia pekinensis , for example, cause irritation of the skin, oral, and gastrointestinal mucosa in humans [ 91 ], as well as nephrotoxicity when in long term use or taking in great quantity [ 92 ]. Livestock may be poisoned by feeding on species of Euphorbiaceae (spurge) that contain irritant diterpene ester toxins [ 93 ], and their milk cause intoxication and even death when consumed by children [ 93 ]. These diterpenes may also act as tumor promoters as a result of direct or indirect exposure through consumption of animal products containing toxic compounds [ 94 ].…”

Biologically active diterpenes containing a gem-dimethylcyclopropane subunit: an intriguing source of PKC modulators

“…41 Jatropherol-I (34) was highly toxic to silkworm larvae, 42,43 moreover compounds 35-51 acted as irritants. [44][45][46][47][48][49][50] On the other hand, compounds 52-59 exhibit molluscicidal activity against the snail, Biomphalaria glabrata. This snail is the major intermediate host for Schistosoma mansoni, one of the important schistosomes infecting man.…”