Medicinal Plants Classification Biosynthesis and ... - Index of

Pharmacologic Study of Some Plant Species from The Brazilian Northeast
RECs, could contribute to the development of pulmonary edema and other lung vascular
changes seen in rats treated with MCT or MCTP.
MCT causes anxiolitic effects at acute doses of 50 and 100 mg/kg (i.p.) in Swiss mice. It
lacks sedative activity (Honório-Júnior et al., 2008).
The exact mechanism of MCT toxicity is not known, but it is necessary that its
biotransformation by liver yields the reactive metabolite DHM, which interferes in DNA and
protein synthesis (Petry et al., 1984, Butler et al., 1970).
6.4. Possible action Mechanism
According to Mattocks (1986), hepatotoxicity of PA is related to insaturation between
carbons 1 and 2, which, in presence of oxidase, yield pyrroles. They bind to nucleophilic
groups of macromolecules, as sulfhydryl, hydroxyl and amino groups of enzymes, globulin,
hemoglobin, purine and pyrimidine. Thus, they make irreversible crosslinks with DNA and
RNA and cause citotoxic, mutagenic and carcinogenic (Nobre et al., 2004a; Simões et al.,
2004).
PA are activated in vivo to yield reactive pyrrolic intermediates that have been shown to
cross-link DNA primarily (Kosogof et al., 2001; Tepe, Williams, 1999). Thus, MCT requires
bioactivation to DHM (Figure 4) by P450 cytocrome in liver, a bifunctional reaction of an
alkaline agent that binds to DNA in vivo. DHM seems to be neutralized by conjugation with
glutathione (GSH). This way, amino acids like cistein, which contains sulfil and taurine,
prevent the toxic effects of MCT (Yan, Huxtable, 1995).
Figure 4. Structures of monocrotaline and dehydromonocrotaline.
Oxidation of substrate linked to energy reduces the equivalent products, which are
transferred via NADH or FADH2 in respiratory chain. An electrochemical proton gradient has
the membrane potential as main component able to maintain ATP synthesis (Nicholls, 1982).
Such connection with mitochondria has been considered an important target to
xenobiotics that can cause cell injuries via ATP depletion (Wallace, Starkov, 2000).
Tepe and Williams (1999) described the semisynthesis and DNA cross-linking of the first
photochemically triggered progenitor of dehydromonocrotaline. A wide variety of
pyrrolizidine alkaloids, such as monocrotaline, and the clinically significant mitomycins and
the related FR-900482, FK 973, and FR-66979 exert their cytotoxicity through the formation
233