Safety evaluation of certain food additives - ipcs inchem

374 ALKOXY-SUBSTITUTED ALLYLBENZENES
GST activity in the liver increased 4.3-fold and in the small intestine 3.2-fold
after 10 mg of myristicin was given by gavage to female A/J mice every 2 days for
a total of 30 mg (Zheng et al., 1992).
Albino mice given doses of myristicin (5–50 mg) by gavage showed a 4- to
14-fold increase in liver GST activity over the control. An increase in GST activity
towards 2,4-dichloronitrobenzene and an increase in the levels of GST μ on western
blot analysis of the myristicin-treated mouse liver suggest a preferential induction
of GST μ. Of the two GST μ subunits expressed in liver, only one was significantly
elevated. Myristicin treatment caused a slight change in the GST levels, whereas
the levels of GST showed a modest increase (Ahmad et al., 1997).
2.1.5 Oxidative stress and cytotoxicity
Oxidative stress and the protective effects of glutathione have been reported
in animals exposed to alkoxy-substituted allylbenzenes.
A dose-dependent increase in the formation of hepatic lipid hydroperoxides
(LHP) and 8-hydroxy-2-deoxyguanosine (8-OH-dG) was reported when Sprague-
Dawley rats were given single intraperitoneal injections of 0, 250, 500 or 1000 mg
safrole/kg bw. LHP peaked on day 3 and gradually returned to the basal level on
day 15. Levels of 8-OH-dG peaked on day 5 and returned to the basal level on day
15. Safrole administration was associated with increased serum alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Dietary
supplements of the antioxidants vitamin E, deferoxamine and N-acetylcysteine
reduced safrole-induced oxidative damage, with the glutathione precursor Nacetylcysteine
exerting the greatest protective effect. Addition of the glutathione
synthesis inhibitor, buthionine sulfoximine, enhanced the safrole-induced oxidative
damage, as evidenced by the elevation of LHP and 8-OH-dG levels on day 3 (P <
0.05). These findings suggest that, at high doses, safrole treatment induces
oxidative damage in rat hepatic tissue, and that glutathione plays a protective role
(Liu et al., 2000).
The associations of genetic polymorphisms of SULT1A1, GSTM1, GSTT1
and GSTP1 with DNA oxidative damage were evaluated among betel quid chewers
exposed to significant levels of safrole. Safrole can be bioactivated by hepatic
sulfotransferase 1A1 (SULT1A1) or detoxicated by GSTs (GSTM1, GSTT1 and
GSTP1). A biomarker for oxidative stress, urinary 8-OH-dG level, was analysed
using isotope dilution liquid chromatography/tandem mass spectrometry (LC–MS/
MS) in 64 betel quid chewers and 129 non–betel quid chewers. Data on
demographics and habits (smoking, alcohol drinking and betel quid chewing) were
obtained from questionnaires. Urinary 8-OH-dG levels were higher in chewers with
SULT1A1 Arg-His genotype than in chewers with SULT1A1 Arg-Arg genotype.
Urinary 8-OH-dG levels were also higher in chewers with GSTP1 Ile-Ile genotype.
Furthermore, the combined effect of SULT1A1 and GSTP1 genotypes on urinary
8-OH-dG was evaluated. Non-chewers with both SULT1A1 Arg-Arg and GSTP1
Val-Val/Ile-Val (reference group) had the lowest mean 8-OH-dG level (3.6 ng/mg
creatinine), whereas chewers with either SULT1A1 Arg-His or GSTP1 Ile-Ile had
the highest mean 8-OH-dG level (6.2 ng/mg creatinine; versus reference group,