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YANNICK GOUMON Y COLS. AN. R. ACAD. NAC. FARM.

condensation of dopamine and 4-hydroxyphenylacetaldehyde
(DOPAL), both of which are derivatives of tyrosine (64). This reaction
proceeds spontaneously in an aqueous environment without
catalysis. It is worth noting that the enzyme CYP2D6 is important
because it is known to be involved in the formation of dopamine
from tyramine, and the conversion of codeine to morphine (67). At
this time, experimental results suggest that this enzyme is present in
the liver, kidneys and immune cells (human white blood cells) (68).
It seems that, as in plants, mammals have two ways of synthesising
morphine from thebaine (Figure 2) although only a few of the
enzymes actually involved in this pathway have been characterised
and much information has been extrapolated from data about
enzymes discovered in plants.

It is also worth noting that dopamine can be synthesised from
tyramine through the action of DOPA decarboxylase/L-aromatic
amino acid decarboxylase so the possibility that cells deficient in
tyrosine hydroxylase (TH) could generate dopamine and therefore
morphine cannot be ruled out. This is all the more likely given
that TH-deficient neurones expressing DOPA decarboxylase (and
therefore capable of producing morphine) have been described in
different parts of the brain (69-73).

Recently, Bianchi et al. conducted experiments on conditional
tyrosine hydroxylase knockout mice [i.e. in which expression of the
gene is only abolished in central dopaminergic neurons (63)]. In the
brains of conditional TH-/- mice, morphine was below the detection
limit of the assay. However, the detection limit was relatively high and
it cannot be excluded that some morphine was present; unfortunately,
no immunohistochemical analysis was performed to complement
these findings. In practice, non-dopaminergic/catecholaminergic cells
such as those of the DAN-G line (pancreas) and HepG2 (hepatocytes)
(66) are capable of producing morphine de novo, and it cannot
be ruled out that morphine may also be synthesised by other cells
in the central nervous system in a pathway dependent on DOPA
decarboxylase or on an unknown enzyme rather than TH. In addition,
it can also not be excluded that some particular cells are able to uptake
morphine precursors (i.e. dopamine) to form morphine.

By means of immunohistochemical analysis, high-performance
liquid chromatography (HPLC) and mass spectrometry, it has been

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