Water‐soluble 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin complex with human α‐fetoprotein: properties, toxicity in vivo and antitumor activity in vitro

Abstract

The conditions for the formation of a non-covalent complex between 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the human transport fetal protein, K K-fetoprotein (AFP), have been studied. TCDD has been shown to form a stable complex with AFP in a 2:1 (TCDD :AFP) ratio. The apparent solubility of TCDD in water increases 10 5 -fold after complex formation. The toxicity of the TCDD:AFP complex injected into mice by the intravenous route is comparable with that of free TCDD administered in oil solution per os. The complex manifests very much higher toxicity (200^1400 times) against human tumor cells (CEM, MCF-7, HepG2) in vitro and surpasses TCDD in selectivity. AFP may facilitate TCDD transport in embryonic tissues and enhance its embryotoxic and teratogenic effects.z 1999 Federation of European Biochemical Societies.

Alpha-fetoprotein Structure and Function: Relevance to Isoforms, Epitopes, and Conformational Variants

“…HAFP has been selected as a vector for specific delivery of anticancer drug conjugates to target cells in vivo as mentioned above; this strategy was based on the overexpression of AFP receptors on the surface of malignant cells Versus the negligible incidence on normal cells (263,265). Due to the bystander effect on surrounding cells, designing of drugs that target solely tumor cell populations is a principal objective in the field of cancer chemotherapy.…”

“…Such agents now include the phytoestrogens, dioxins, and the flavinoids. Binding of rodent and HAFP to the phytoestrogens has previously been discussed and the reader is directed to these references (6,265,267). Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD)) belongs to a class of highly hazardous environmental contaminants formed as a by-product of technological manufacturing processes.…”

“…Such compounds are also embryotoxic, teratogenic, neurotoxic, and immunotoxic in a multitude of target organs (i.e., thymus, spleen, lymph nodes, adrenal, thyroid, mammary, and sex accessory glands). This highly embryotoxic agent has been found to form a noncovalent, stable complex with HAFP in a 2: I ratio (265). The apparent solubility of TCDD in water increases 10 5 fold after binding to HAFP and the injected water-soluble complex is less cytotoxic in normal mice than TCDD injected in oil suspensions.…”

Can resveratrol attenuate testicular damage in neonatal and adult rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin during gestation?

“…Induction of CYP 1A1 in the placenta during pregnancy due to AhR ligands has been reported previously (Stejskalova and Pavek 2011). Moreover, TCDD has been shown to form a stable complex with a-fetoprotein, which, in turn, may favour the transport of TCDD across the placenta, consequently contributing to its teratogenic effects (Sotnichenko et al 1999).…”

The Use of AFP-Complexes to Induce Apoptosis in Cancer Cells~!2008-03-12~!2008-05-20~!2008-06-12~!

“…F or t he addressed de livery of t he AI, we have us ed AF P which ha s highly s pecific re ceptors re -expressed on the m ajority o f cancer cells [19] and is up taken by them [20]. AFP-mediated de livery of di oxin to c ancer c ells h aving AFP re ceptor (AF PR) wa s 200-1400 t imes more effective than di oxin a lone [12]. T he e nvironmental t oxin di oxin is itself carcinogenic [21] a nd is not a direct AI, so its anticancer application is problematic.…”