Hepatic Protective Effects of <i>S</i>-Allyl-L-Cysteine (SAC) in Rats with Carbon Tetrachloride (CCl₄) Induced Liver Injury

S-allyl-L-cysteine (SAC) is an organosulfur compound derived from aged garlic extract (AGE). Studies have reported that AGE possesses bioprotective capacity, including antidiabetic, antimicrobial, antioxidant, and antitumor effects. The present study examined the protective effects of SAC against carbon tetrachloride (CCl4) induced hepatotoxicity in rats. Ten male Wistar rats aged 11 - 12 weeks were randomly divided into two groups (five rats/group) as control and SAC groups. All rats had ad libitum access to water, and the SAC group received water containing SAC intragastrically (200 mg/kg) once daily for five consecutive weeks. In the fifth experimental week, 50% CCl4 in olive oil (1 mL/kg) was administered intraperitoneally three times a week to induce liver injury in both groups. Rats were sacrificed at 24 hours after the last CCl4 injection, and liver tissues were excised for histopathological, immunohistochemical and antioxidant analyses. The rats in the SAC group did not show abnormal behavior, such as decreased water intake or food consumption, during the experimental period. Body weights in all groups did not change significantly over the experimental period. Histopathological analysis showed that the percentage of hepatic steatosis was lower in the SAC group at 12.75% ± 3.74% compared to 24.64% ± 5.29% in the control group (p < 0.05). The percentage of cytochrome P4502E1 (CYP2E1) distribution area in the SAC group was also lower at 19.61% ± 6.18% compared with 25.22% ± 6.21% in the control group (p < 0.05). These results suggest that SAC can alleviate CCl4-induced liver damage by decreasing hepatic steatosis and reducing CYP2E1 expression in rats.

Oxidative stress and breast cancer biomarkers:the case of the cytochrome P450 2E1

Aim:The aim of the study is to investigate the impact of the cytochrome P4502E1,which is the most efficient CYP450 family member in generating reactive oxygen species(ROS),on cellular energy metabolism of breast cancer cells and therefore the effects of CYP2E1 on breast carcinogenesis.Methods:The estrogen receptor positive MCF-7 and the triple negative MDA-MB-231 breast cancer cells were used as experimental system to estimate ROS generation in these cells overexpressing CYP2E1 and treated with the glycolytic inhibitors 3-bromopyruvate or 2-deoxyglucose in the presence or absence of the CYP2E1 inhibitor chlormethiazole.Adenosine triphosphate(ATP)assay was used to measure ATP production and lactate assay to quantify the efflux of lactic acid in breast cancer cells treated with the CYP2E1 inhibitor chlormethiazole,the mitochondrial membrane potential and cell viability assays were employed to assess the pathway of cellular energy production and cellular death respectively after treatment of MCF-7 and MDA-MB-231 with the CYP2E1 activator acetaminophen or the CYP2E1 inhibitor chlormethiazole.Results:T he r esults i ndicated i ncreased ROS generation i n b reast c ancer c ells overexpressing C YP2E1.ROS generation was differentially regulated in breast cancer cells upon treatment with the CYP2E1 inhibitor chlormethiazole.Chlormethiazole treated MCF-7 cells exhibited reduced lactate efflux implying that CYP2E1 directly or indirectly regulates the glycolytic rate in these cells.Furthermore the mitochondrial membrane potential of both MCF-7 and MDA-MB-231 cells was differentially affected by the CYP2E1 activator acetaminophen versus the CYP2E1 inhibitor chlormethiazole providing additional support for the involvement of CYP2E1 in energy metabolic pathways in breast cancer.Conclusion:Results presented in this study provide evidence to suggest that CYP2E1 regulates cellular energy metabolism of breast cancer cells in a manner dependent on cell type and potentially on the clinical staging of the disease therefore CYP2E1 is a possible breast cancer biomarker.

Hepatocellular carcinoma in alcoholic liver disease: mechanistic considerations and clinical facts

Alcoholic hepatocellular carcinoma(AHCC)represents a lethal stage,emerging in the course of severe injurious stages of alcoholic liver disease including cirrhosis.AHCC only affects a few alcohol consumers,certainly not all individuals who consume large amounts of alcohol over a long period of time,suggesting a role of yet unknown genetic risk or protection factors.Most likely,hepatic DNA is ultimately involved,attacked by intermediate products derived from reactive oxygen species(ROS)generated from cytochrome P4502E1 of the NADPH and oxygen dependent microsomal ethanol-oxidizing system whereby ethanol is metabolized.Ethanol and acetaldehyde are activated to procarcinogens,to be promoted to ultimate carcinogens by ROS and causatives for AHCC instead of any other putative chemical contained in alcoholic beverages.Prevention of HCC associated with cirrhosis is best accomplished by early recognition of alcohol abuse at the stage of alcoholic fatty liver rather than alcoholic hepatitis(AH)or alcoholic steatohepatitis(ASH),leading to the advice of consequent abstinence from alcohol.Abstinence early started effectively prevents AHCC development,as opposed to late begin of abstinence that lacks risk reduction.Although drug therapy may partially be effective in AH or ASH,no established drug options are available for a realistic therapy of AHCC.Liver transplantation is controversially discussed and can be considered,but may be an option for only a few patients on a case by case base.In conclusion,AHCC results from a ROS dependent conversion of ethanol and acetaldehyde to procarcinogens as promoters of AHCC.