Chemical Implications for Antitumor and Antiviral Prostaglandins:  Reaction of Δ⁷-Prostaglandin A₁ and Prostaglandin A₁ Methyl Esters with Thiols

Abstract

Prostaglandins (PGs) such as Δ12-PGJ2 and Δ7-PGA1 methyl ester that possess a cross-conjugated dienone unit exhibit unique antitumor and antiviral activities independent of intracellular cAMP levels. These compounds are transported reversibly into cultured cells and accumulate in nuclei via covalent interaction, eliciting growth inhibition. PGA1 methyl ester, a simple cyclopentenone analog, is less potent. The unique cellular behavior of the dienone PGs correlates well with their chemical properties. The PGs react specifically with thiol nucleophiles such as glutathione. Michael addition of thiols to Δ7-PGA1 methyl ester, an alkylidenecyclopentenone derivative, occurs facilely at the endocyclic C(11) position rather than at the C(7) position. This process is reversible, and in solution phase, the adducts are in equilibrium with considerable amounts of free PG and thiols. However, the reaction of this PG with Sepharose-bound thiols, regarded to be plausible mimics of protein thiols, is irreversible, and the resulting adducts are dissociated only by alkali treatment. On the other hand, PGA1 methyl ester reacts with soluble or polymer-anchored thiols at lower rates than Δ7-PGAl methyl ester, but the resulting thiol adducts are substantially more stable than those of the dienone PGs. This tendency of the PGA1 methyl ester causes its equilibrium to shift to the adduct formation. The reversibility of the Michael reaction of PGs with thiols is consistent with their intracellular behavior and biological activities. Since glutathione adducts of PGs have no antiproliferative activities for cancer cells, the intracellular free PGs are presumed to interact with target molecules to cause cell growth inhibition. The involvement of the ATP-dependent glutathione S-conjugate export pump (GS-X pump) in the efflux of PGs is discussed. Thus, the marked difference in potency of the dienone and enone PGs is explained by considering the combined kinetic and thermodynamic properties and the action of the GS-X pump.

In situ studies on the bioaccumulation of microcystins in the phytoplanktivorous silver carp (Hypophthalmichthys molitrix) stocked in Lake Taihu with dense toxic Microcystis blooms

“…Similarly, an immunostaining study showed that the injected conjugates (MCLR-GSH and MCLR-Cys) were prominently observed in the intestine and kidney of mice (Ito et al, 2002). In their experiment, no effective accumulation of the injected conjugates in the liver was found in spite of the larger dosage, and the toxins might be effectively eliminated by an appropriate system such as the GS-X (ATP-dependent glutathione S-conjugate exported) pump (Suzuki et al, 1997). This may explain why we could not find MCLR-Cys in the liver samples of silver carp in the present study.…”

Cytoprotective Function of Heme Oxygenase 1 Induced by a Nitrated Cyclic Nucleotide Formed during Murine Salmonellosis

“…It was recently reported that intracellular concentrations of 15d-PGJ 2 formed endogenously is as low as 1 nM (57). Furthermore, cysteine adducts of 15d-PGJ 2 are so unstable to readily dissociate spontaneously under physiological conditions (58). These factors may hamper detection of Keap1-PGJ 2 adducts.…”

In situ studies on the distribution patterns and dynamics of microcystins in a biomanipulation fish – bighead carp (Aristichthys nobilis)

“…An immunostaining study (Ito et al, 2002) showed that the injected conjugates (MCLR-GSH and MCLRCys) were prominently observed in the intestine and kidney of mice, whereas effective accumulation and bleeding were not found in the liver in spite of the larger dosage. They presented two reasons for this: firs, the transport system to the liver does not function well, second, the transported toxins are effectively eliminated by an appropriate system such as the GS-X (ATP-dependent glutathione S-conjugate exported) pump (Suzuki et al, 1997). They also reported that MCLR-Cys was detected in kidney soon after the injection and continued to be strongly detected for 1 h, and concluded that MCLR-Cys was the most actively excreted from the kidney.…”