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EC number: 203-815-1
CAS number: 110-91-8
this report including in vivo and in vitro metabolism studies, the
metabolism of Morpholine was assessed through the investigation of
subcellular binding interactions, nitrosamines generation as part of
Morpholine metabolism, biologically active Morpholine metabolites in a
UDS assay, the biochemical basis for species differences noted in
Morpholine metablism, and the differences in human, rat, hamster and
guinea pig liver capacity for Morpholine metabolism.
A uniform distribution of 14C in
TCA-insoluble fractions indicated a non-specific binding and/or
incorporation of Morpholine. No significant amounts of covalently bound
14C were detected in the subcellular fractions of the liver. Very
little, if any, radioactivity derived from 14C Morpholine was bound to
liver DNA. Therefore, it was concluded that the TCA-insoluble
macromolecules of the nuclear fraction probably reflected the 14C
associated with proteins and/or RNA. The results did not provide
evidence for the in vivo formation of N-nitrosomorpholine after
administration of Morpholine under the conditions described. In vivo
methylation of Morpholine (step 1 in the metabolism process) proceeded
via the SAM pathway. Guinea pig liver microsomes showed the most
metabolic activity in vitro. Ziegler's flavin monooxygenase was
exlusively involved in the N-oxidation of N-methylmorpholine and at
least partially so in the N-hydroxylation of Morpholine and was evidence
against the involvement of cytochrome P450 in these reactions. Of the
species examined, human liver most resembled that of the rat in its
ability to metabolize Morpholine.Morpholine
was not bound to serum proteins.
metabolism study is classified as acceptable.
1. In the initial part of this study, the
amount of 14C in the tissue macromolecules, expressed as µg eq. of
Morpholine/g tissue, remained rather constant in all organs throughout a
24 hour period. In contrast, the total radioactivity determined in the
whole tissue homogenates (representing bound plus unbound forms)
declined rapidly with time. Since a considerable amount of 14C was found
to be present in fractions from the liver and kidney homogenates, a
second phase was conducted to determine whether there was preferential
uptake in some particular subcellular fraction. While cytosol contained
the highest level of 14C (expressed in terms of ng eq. Morpholine/µg
protein) in both the liver and kidney, when 14C was determined in
various subcellular fractions no signficant differences among these were
2. The specific activity of the DNA was 31
and 29 dpm per mg DNA for 4 and 24 hours, respectively. The U.V.
absorption monitored at 260 nm clearly demonstrated the presence of
guanine and adenine, eluted at 6 and 12 mL and pyrimidine
oligonucleotides eluting between 2 and 5 mL, respectively. However, no
significant radioactivity associated with either peak or at any other
elution volume were detected.
3. In no case was any radioactivity above
background found to be associated with N-nitrosomorpholine peak in
either HPLC system.
4. Not applicable.
5. When N-methylmorpholine-N-oxide was
isolated from the urine (in vivo), 10.5 % of the radioactivity of the
L-[methyl-14C]-methionine administered was found to be incorporated in
the metabolite. When tested in vitro, the initial rate of formation of
N-methylmorpholine by guinea pig liver cytosol was approximately 0.13
nmol/min/mg protein, while the rate using hamster liver cytosol was less
than 1/10 of this and was almost undetectable using rat liver cytosol.
When evaluating the metabolic rates of oxidation of N-methylmorpholine
to N-methylmorpholine-N-oxide or of Morpholine to N-hydroxymorpholine,
the N-hydroxylase activity was almost undetectable using rat liver
microsomes; however, hamster liver microsomes contained significant
levels of this enzyme and guinea pig liver microsomes were even more
active. When the liver microsome catalyzed N-oxidation of
N-methylmorpholine was evaluated, liver microsomes from the guinea pig
were more active than those from the hamster, which, in turn, were more
active than rat liver microsomes. While the species differences in the
rates of N-oxidation were not as marked as those observed in the case of
N-methylation or N-hydroxylation of Morpholine, a similar pattern was
observed, with liver microsomes from the guinea pig being more active
than those from the hamster, which, in turn, were more active than rat
liver microsomes. When in vitro incubations were conducted in the
presence of methimazole, SKF 525 -A and liver microsomes, SKF 525 -A
failed to inhibit N-hydroxylation of Morpholine and the N-oxidation of
N-methylmorpholine; however, methimazole inhibited the N-hydroxylation
by approximately 60 % and almost completely blocked the N-oxidation of
6. Using human liver cytosols, no detectable
Morpholine N-methylase activity was found. When the formation of
N-methylmorpholine-N-oxide from N-methylmorpholine was monitored using
microsomes, human livers were found to be active in carrying out this
reaction, though the activity was lower than that observed with rat
liver. In addition, studies using enzyme modifiers showed that the
reaction was inhibited 70% by methimazole, indicating that the
flavin-containing monooxygenase was also involved in the human liver in
carrying out this reaction. Determination of Morpholine hydroxylase
indicated that the human liver microsomes were able to N-hydroxylate
Morpholine, with an activity of approximately 0.008 µmol/mg protein/30
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