Modulation of cytochrome P450 enzymes by organosulfur compounds from garlic.
Organosulfur compounds (OSCs) derived from garlic have been studied for the ability to inhibit experimental cancer in various animal models, primarily through modification of carcinogen detoxification enzymes, such as cytochrome P450 (CYP) enzymes. OSCs vary in structural and physical properties, and a detailed analysis of these properties has not been performed with respect to their ability of inhibit chemically-induced colon cancer development. Gastric intubation of rats with a single dose of 200 mg/kg diallyl sulfide (DAS), diallyl disulfide (DADS), and allyl methyl sulfide (AMS) decreased hepatic CYP2E1 protein by 45%, 25% and 47%, respectively, and this inhibition was sustained after 1, 4 and 8 weeks of treatment by these compounds. Dipropyl sulfide (DPS), dipropyl disulfide (DPDS), propyl methyl sulfide (PMS) and S-allylcysteine (SAC) did not inhibit hepatic CYP2E1 protein expression, nor did any of the OSCs affect CYP2E1 mRNA levels. A single dose of 200 mg/kg DAS and AMS increased hepatic CYP1A2 protein (but not mRNA) by 282% and 70%, and DAS increased CYP1A1 protein levels by 684%. Daily treatment for 1, 4 and 8 weeks with 200 mg/kg DAS and AMS resulted in time-dependent increases in hepatic CYP1A1 and CYP1A2 protein levels to a maximum of 600% and 50% for DAS, and 1600% and 240% for AMS after 8 weeks. Dosing with 200 mg/kg of each of the OSCs used in this study increased hepatic CYP3A2 protein levels at all time points. Dosing for 8 weeks with 200 mg/kg DAS, but not AMS or lower doses of DAS, induced bile duct obstruction and focal areas of necrosis. These results indicate that OSCs present in garlic, including DAS and AMS, may be beneficial in inhibiting chemically-induced colon cancer, but that longer dosing with higher concentrations of DAS may elicit minor hepatic toxicity.
Davenport
Destiny M
DM
Department of Pathology and Microbiology, University of South Carolina, School of Medicine and South Carolina Cancer Center, Columbia, SC 29208, USA. matthew2@niehs.nih.gov
Wargovich
Michael J
MJ
D000498:Allyl Compounds / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000633:toxicity; D015197:Carcinogenicity Tests; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004220:Disulfides / Q000494:pharmacology / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005737:Garlic / Q000737:chemistry*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D013440:Sulfides / Q000494:pharmacology / Q000633:toxicity; D013457:Sulfur Compounds / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors
D000498:Allyl Compounds; D016588:Anticarcinogenic Agents; D004220:Disulfides; D013440:Sulfides; D013457:Sulfur Compounds; C028009:diallyl disulfide; C038491:allyl sulfide; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; C077207:allyl methyl sulfide