Safety evaluation of certain food additives - ipcs inchem

ALKOXY-SUBSTITUTED ALLYLBENZENES 373
1-fold increase in hamsters and a 3-fold decrease in mice. Myristicin caused a
4-fold increase in EROD activity in rat liver, nearly half the increase seen for safrole.
No increase in EROD activity in the lung or kidney was observed for either
substance (Iwasaki et al., 1986).
Myristicin was administered to groups of four male Sprague-Dawley rats at
doses of 10–5000 μmol/kg bw by intraperitoneal injection. A dose-dependent
increase of CYP activities was reported, reaching a maximum at 500 μmol/kg bw.
At that concentration, the activity reached a maximum at 24 h for CYP1A1/CYP1A2
and CYP2B1/CYP2B2 and at 12 h for CYP2E1. Immunoblotting analysis indicated
that the increase in CYP enzyme activities was accompanied by increases in CYP
apoprotein content, and northern blot analysis showed that the induction of
CYP1A1/CYP1A2 and CYP2B1/CYP2B2 was also accompanied by a
corresponding increase in messenger ribonucleic acid (mRNA) encoding these
proteins. For CYP2E1, induction was not accompanied by an increase in CYP2E1
mRNA (Jeong & Yun, 1995).
In a study of the reversible and irreversible inhibition of isoenzymes of GST
by alkoxy-substituted allylbenzenes, purified -, μ- and -class isoenzymes of GST
(10–30 nmol/l) prepared from rat and human liver were incubated with different
concentrations of methyl eugenol and other hydroxy- and methoxyallylbenzene
derivatives. Immediately after incubation, conjugation activity was measured using
1-chloro-2,4-dinitrobenzene as a substrate. In rat liver, all classes of GST
isoenzymes were most strongly inhibited by methyl eugenol, whereas in human
liver, GST inhibition capacity was similar for all allylbenzene derivatives
(Rompelberg et al., 1996).
In studies probing the effect of structure, species and CYP enzyme induction,
incubation of methyl eugenol with rat and human liver microsomes indicates that
1-hydroxylation is catalysed predominantly by CYP2E1 and probably CYP2C6. The
rate of 1-hydroxylation of methyl eugenol varied widely in 13 human liver microsome
samples (37-fold), but the highest activities were similar to the activities in control
rat liver microsomes (Gardner et al., 1997a). At low substrate concentrations in
control rat liver microsomes, 1-hydroxylation of methyl eugenol was induced by
phenobarbital, isosafrole and dexamethasone, but significantly inhibited by
diallylsulfide (40%), -naphthoflavone (25%) and p-nitrophenol (55%).
Treatment of mouse hepatoma Hepa-1c1c7 (Hepa-1) cells with myristicin
increased CYP1A1 transcription in a dose-dependent manner, as shown by
analysis of EROD activity, quantification of CYP1A1 protein levels and
determination of CYP1A1 mRNA levels. In a competitive aryl hydrocarbon (Ah)
receptor binding analysis, myristicin did not competitively displace [ 3 H]2,3,7,8tetrachlorodibenzo-p-dioxin
from the Hepa-1 cytosolic (Ah) receptor, and it did not
affect formation of DNA–protein complexes between the Ah receptor and its dioxinresponsive
enhancer (DRE) target in a gel mobility shift assay using
oligonucleotides corresponding to DRE 3 of CYP1A1. These results suggest that
induction of CYP1A1 in Hepa-1 cells by myristicin might occur through an Ah
receptor–independent pathway (Jeong et al., 1997).