Mechanisms of Inhibition of Chemical Toxicity and Carcinogenesis by Diallyl Sulfide (DAS) and Related Compounds from Garlic

Abstract

Diallyl sulfide (DAS) is a flavor compound derived from garlic and is sequentially converted to diallyl sulfoxide (DASO) and diallyl sulfone (DASO(2)) by cytochrome P(450) 2E1 (CYP2E1). These compounds have been shown to reduce the incidence of a multitude of chemically induced tumors in animal models. The impediment of phase I activation of these carcinogens is hypothesized to be accountable for the reduction in tumor incidence. Indeed, DAS, DASO and DASO(2) are competitive inhibitors of CYP2E1. DASO(2), in addition, is a suicide inhibitor of CYP2E1. These compounds have been shown to reduce carbon tetrachloride-, N-nitrosodimethylamine- and acetaminophen-induced toxicity in rodents. All three chemicals are substrates for CYP2E1. The protective effect was observed when the organosulfur compounds were given before, during or soon after chemical treatment. DAS and DASO(2) inhibited the bioactivation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and related lung tumorigenesis in A/J mice. Because CYP2E1 does not play a key role in NNK activation, the inhibition of other CYP enzymes active in NNK metabolism is likely. DAS also has been shown to induce other CYP and phase II enzymes as well as decrease hepatic catalase activity. All of these effects are observed at concentrations much higher than what is normally ingested by humans. The biological activities of garlic and its related compounds at lower concentrations that mimic human consumption remain to be studied further.

Diallyl sulfide induces cell cycle arrest and apoptosis in HeLa human cervical cancer cells through the p53, caspase- and mitochondria-dependent pathways

“…Garlic (Allium sativum L.), is widely used as foodstuff and medicine throughout the recorded history (5). Based on epidemiologic, clinical, and laboratory studies we have indicated that Allium vegetables and/or their constituents contain biological activities that stimulate immune function Diallyl sulfide induces cell cycle arrest and apoptosis in HeLa human cervical cancer cells through the p53, caspase-and mitochondria-dependent pathways (6,7), reduce the risk of cardiovascular diseases (8)(9)(10)(11), change blood glucose level (12,13) anti-microbial, viral and fungal infections (14)(15)(16), anti-aging effects (17,18), anti-cancer function (19)(20)(21) and anti-tumorigenesis effects (22). Increasing evidences has suggested that the mechanism of anti-cancer action of garlic compounds may involve modulation of signal transduction pathways (23).…”

Chemopreventive Effects of Nobiletin against Genotoxicity Induced by 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the Lung of gpt delta Transgenic Mice

“…Since MNNG induces O 6 -methylguanine leading to G:C-to-A:T mutations (38), we suggest that nobiletin may not enhance the repair activity against O 6 -methylguanine or promote error-free translesion bypass across the lesion. Instead, we suggest that nobiletin may suppress the genotoxicity of NNK by inhibiting the activity of CYP (P-450) enzymes involved in the metabolic activation of NNK (39)(40)(41). In fact, 8-methoxypsoralen, a speciˆc-inhibitor of CYP2A, similarly suppressed the genotoxicity of NNK in the presence of S9 enzymes (23).…”

Cytochrome P4502E1 primes macrophages to increase TNF-α production in response to lipopolysaccharide

“…DPI, an inhibitor of NADPH oxidase complex (12,17,38), inhibited most of the oxidase activity in E2 and M1 cells, consistent with the action of the inhibitor. DAS, a CYP2E1 inhibitor (3,54), halved the oxidase activity in E2 cells, suggesting involvement of CYP2E1, at least in part, in the stimulation of NADPH oxidase activity in E2 cells, but it had no effect on the oxidase activity in M1 cells, reflecting the absence of CYP2E1. LPS/LBP treatment raised the oxidase activity in both E2 and M1 cells compared with corresponding untreated cells (Fig.…”