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Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore
) in the April issue of
Drug Metabolism and Disposition reported that thalidomide inhibited
the proliferation of embryo fibroblasts in the presence of microsomes from
rabbit liver or HepG2 cells pretreated with 3-methylchlolanthrene (3-MC).
Mouse liver microsomes or microsomes from human HepG2 cells pretreated with
vehicle did not cause inhibition. The inhibition was abolished by the addition
of 
-naphthoflavone, furafylline, or anti-rat CYP1A1 antibody. The
authors concluded that CYP1A1 was responsible for the bioactivation of
thalidomide to a reactive metabolite that resulted in inhibition of embryo
fibroblast proliferation.
However, the data provided by the authors could not exclude the involvement
of CYP1A2 in the bioactivation of thalidomide. In fact, the majority of human
CYP1A inhibitor and substrate probes are nonspecific in their recognition of
CYP1A1 and CYP1A2 with significant species differences
(Tassaneeyakul et al., 1993;
Eagling et al., 1998). For
example, -naphthoflavone inhibited CYP1A1- and 1A2-mediated phenacetin
O-deethylation (Tassaneeyakul et
al., 1993); furafylline as a selective inhibitor of CYP1A2 in
humans can inhibit both CYP1A2 and 2C9 in rats
(Eagling et al., 1998).
Furthermore, anti-rat CYP1A1 antibody preparations can recognize CYP1A1/1A2
from the rat and other species (Zhou et
al., 2000). As shown in Fig. 8, in Miyata et al.
(2003) the existence of small
amounts of CYP1A2 in microsomes from HepG2 cells treated with 3-MC (lanes 3
and 5 of Fig. 8B) is likely. 3-MC has been shown to induce CYP1A2 in HepG2
cells (Quattrochi et al., 1994;
Pickwell et al., 2003), which
may be attributable to the interaction of upstream enhancing factors with an
E-box within the CYP1A2 5'-flanking gene
(Pickwell et al., 2003). An
increase in treatment time of HepG2 cells with 3-MC (24 h in this study) would
allow the expression of CYP1A2. Additionally, Fort et al.
(2000) observed enhanced
toxicity of thalidomide to frog embryos in the presence of microsomes from the
rat treated with either isoniazid or Aroclor 1254. However, the addition of
3-amino-1,2,4-triazole or -naphthoflavone ameliorated the toxicity,
suggesting the involvement of CYP1A1/2 and CYP2E1 in thalidomide
bioactivation. It would be interesting to examine whether CYP2E1 is involved
in embryo fibroblast inhibition by thalidomide.
Miyata et al. (2003) did not
report the effect of hydrolysis products of thalidomide on embryo fibroblast
proliferation. Thalidomide undergoes rapid hydrolysis
(Eriksson et al., 2001),
whereas CYP2C19-mediated metabolism (Ando
et al., 2002) is considered to play a minor role. Furthermore,
some studies demonstrated that the biological activities of thalidomide were
dependent on the intact molecule (Shannon
et al., 1997). Hydrolysis of thalidomide will abrogate its
immunomodulating activity.
References
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Graduate School of Pharmaceutical Sciences Tohoku University Sendai, Japan
We thank Dr. Shufeng Zhou for comments regarding our recent publication, Miyata et al. (2003). We are now analyzing human CYP forms involved in thalidomide-induced suppression of embryo fibroblast proliferation and are also identifying the structure of the metabolites. Because we will show these results in a future study, we choose not to respond to the letter at this time.
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