Corsini et al. (1985
) unexpectedly found that diethyldithiocarbamate (DDC), the main metabolite of disulfiram, markedly enhanced the MPTP-induced parkinsonism in mice. This effect was initially interpreted as due to the inhibition of superoxide dismutase leading to an increase in oxidative stress induced by the toxin. Subsequently, among numerous compounds tested, other enhancers of MPTP toxicity (ethanol and ACE) were found by the same authors (Corsini et al., 1987
). After this further discovery, this group suggested that these compounds could increase the potency of the toxin via an inhibition of ALDH within the striatum. The “enhancers,” at the same time, prolonged the striatal half-life of 1-methyl-4-phenylpyridinium ion (MPP+
), the toxic metabolite of MPTP, (Irwin et al., 1987
; Zuddas et al., 1989b
) and this was interpreted as the causative factor of this enhancement. However, in 1996 an article by Vaglini et al. demonstrated that striatal MPP+
levels do not necessarily correlate with MPTP toxicity in the same animal species (mouse) and they further on suggested, as previously reported, that DDC-increased toxicity was probably due to an independent action on glutamate receptors (Vaglini et al., 1996
). However it is likely that the prolonged storage of MPP+
inside the DA neurons was crucial for its toxic effects. According to this interpretation, the enzymes, which may determine the disposition of MPP+
inside the DA neurons, have a cardinal role in MPTP toxicity. CYP 2E1 and the CYP 2D family are the most widely represented isozymes within the DA neurons (Watts et al., 1998
; Riedl et al., 1999
) and it is likely that these two P450 enzymes are responsible for MPP+
clearance. As a matter of fact, DDC, ethanol and ACE have been discovered to be specific substrates/inhibitors of CYP 2E1 when they are acutely administered (Stott et al., 1997
) (Figure ). This specific inhibition inside the DA neuron may account for the increase in MPP+
striatal half-life, and thus toxicity.
Role of CYP 2E1 in metabolizing ethanol and acetaldehyde.
More recently, furthermore, we demonstrated that, similar to DDC and ACE, CYP 2E1 substrates/inhibitors, such as diallylsulfide (DAS) or phenylethylisothiocyanate (PIC) markedly enhance MPTP toxicity in C57/bl brain, suggesting an involvement of CYP 2E1 in the enhancement of MPTP toxicity. However, because DAS and PIC are not true CYP 2E1 inhibitors (Nissbrandt et al., 2001
), in order to provide direct evidence for CYP 2E1 involvement, CYP 2E1 knockout (KO) mice and their wild-type counterparts were challenged with the combined treatment DDC+MPTP (Vaglini et al., 2004
). In that article we consistently showed that an inhibition of the enzyme, as obtained with DDC challenge, failed to enhance the toxic effect of MPTP in CYP 2E1 KO mice, whereas the effect was regularly present in wild-type animals. Focusing on this, we have studied the sensitivity of CYP 2E1 KO mice to the toxin (Viaggi et al., 2009
). The lack of CYP2 E1 did not increase MPTP toxicity as expected from previous experiments with the inhibitors, and, in fact, the CYP 2E1 KO mice showed a significant resistance to DA neuronal lesions induced by the toxin in comparison with their wild-type counterparts. The reduced sensitivity to MPTP of CYP 2E1 KO mice, but not the complete insensitivity, may be due to compensatory mechanisms taking place because of the missing protein. This phenomenon was observed very clearly by Gonzalez when his team generated these mice in order to study acetaminophen-induced liver toxicity (Lee et al., 1996
). This drug causes liver and kidney necrosis when it is metabolized to an alkylating intermediate by the P450 system, and more specifically by CYP 2E1 (Jollow et al., 1973
; Mitchell et al., 1973
; Gonzalez, 2007
). CYP 2E1 KO mice were generated to strengthen the specific role of CYP 2E1 during acetaminophen toxicity (Lee et al., 1996
). The CYP 2E1 KO mice were less sensitive to the hepatotoxicity of the drug but they were not completely unaffected. A compensatory isozyme of the P450, probably CYP2D6, was substituted, thus producing the same—though reduced—toxic effect. Very recently we generated mesencephalic cell cultures from CYP 2E1 KO and wild-type embryos to investigate MPP+
toxicity and its cell distribution. In this model we demonstrated that a trace amount of MPP+
accumulates inside the neurons from KO mesencephalic cultures in a quantity double than that from wild-type embryos, although the KO cultures are less lesioned by the toxin (manuscript in preparation). We then suggested, once inside the cell (or striatal synaptic terminal), MPP+
entered preferentially into vesicles where its storage represented a sort of protection with respect to other toxic sites such as mitochondria.
In conclusion CYP 2E1 may facilitate the transfer of MPP+ to mitochondria for further metabolism. Alternatively and independently from MPP+ disposition, CYP 2E1 produces toxic reactive intermediates from endogenous or exogenous substrates which in turn impair neuronal viability.