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Liver subcellular fractions from rats treated by organosulfur compounds from Allium modulate mutagen activation
D Guyonnet1, C Belloir, M Suschetet
1Institut National de la Recherche Agronomique, Unité de Toxicologie Nutritionnelle, BV 1540, 17 rue Sully, 21034, Dijon, France.
Abstract:
The effects of in vivo administration of naturally occurring organosulfur compounds (OSCs) from Allium species were studied on the activation of several mutagens. Male SPF Wistar rats were given p.o. one of either diallyl sulfide (DAS), diallyl disulfide (DADS), dipropyl sulfide (DPS) or dipropyl disulfide (DPDS) during 4 consecutive days and the ability of hepatic S9 and microsomes from treated rats to activate benzo[a]pyrene (BaP), cyclophosphamide (CP), dimethylnitrosamine (DMN), N-nitrosopiperidine (N-PiP) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was determined in the Ames test. Administration of DAS, DPS and DPDS resulted in a significant increase of the activation of BaP, CP, N-PiP and PhIP mediated by S9 and microsomes while DADS treatment only increased the mutagenicity of PhIP. In contrast, S9 from DADS-treated rats significantly inhibited the mutagenicity of N-PiP and BaP. DAS, DADS and DPS strongly inhibited DMN mutagenicity while DPDS enhanced it. To understand the mechanisms underlying these effects, the modifications of the activities of specific isozymes of CYP involved in the activation of these mutagens were studied. DAS, DPS and DPDS strongly enhanced pentoxyresorufin O-dealkylase (PROD) activity related to CYP2B and slightly increased ethoxyresorufin O-deethylase (EROD) and methoxyresorufin O-demethylase (MROD) activities related to CYP1A family. DADS exerted the same effects than other OSCs but to a lesser extent. p-Nitrophenol hydroxylase (PNPH) activity related to CYP2E1 was inhibited by DAS and DADS, whereas DPDS significantly increased this activity. Hence, the effects of OSCs on the mutagenicity of several genotoxic compounds are mediated by modification (enhancement or inhibition) of specific CYP involved in their activation.
Insights
Naturally occurring organosulfur compounds (OSCs) from Allium species alter mutagen activation in rats. These compounds modify cytochrome P450 enzyme activity, influencing the mutagenicity of various genotoxic substances.
Area of Science:
- Toxicology
- Pharmacology
- Nutrigenomics
Background:
- Organosulfur compounds (OSCs) are bioactive constituents found in Allium species (e.g., garlic, onions).
- OSCs are known for their diverse biological activities, including potential chemopreventive properties.
- The metabolic activation of mutagens is a critical step in chemical carcinogenesis.
Purpose of the Study:
- To investigate the in vivo effects of specific OSCs on the metabolic activation of various mutagens.
- To elucidate the underlying mechanisms by examining the impact of OSCs on cytochrome P450 (CYP) enzyme activities.
Main Methods:
- Male Wistar rats were orally administered diallyl sulfide (DAS), diallyl disulfide (DADS), dipropyl sulfide (DPS), or dipropyl disulfide (DPDS) for four consecutive days.
- Hepatic S9 fractions and microsomes from treated rats were used to assess the activation of mutagens (benzo[a]pyrene, cyclophosphamide, dimethylnitrosamine, N-nitrosopiperidine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) in the Ames test.
- Activities of specific CYP isozymes (CYP1A, CYP2B, CYP2E1) were measured using relevant O-dealkylase assays.
Main Results:
- DAS, DPS, and DPDS significantly increased the mutagenicity of benzo[a]pyrene, cyclophosphamide, N-nitrosopiperidine, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.
- DADS selectively increased the mutagenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine but inhibited that of N-nitrosopiperidine and benzo[a]pyrene.
- OSCs differentially modulated CYP enzyme activities, with DAS, DPS, and DPDS enhancing CYP2B activity and DAS and DADS inhibiting CYP2E1 activity.
Conclusions:
- In vivo administration of OSCs from Allium species significantly alters the metabolic activation of mutagens.
- These modulatory effects are mediated by the differential induction or inhibition of specific cytochrome P450 isozymes.
- OSCs possess the potential to modulate the toxicological outcomes of exposure to genotoxic compounds through their influence on xenobiotic metabolism.