The role of metabolic activation in drug-induced hepatotoxicity.
Park BK, Kitteringham NR, Maggs JL, Pirmohamed M, Williams DP.
Department of Pharmacology and Therapeutics, University of Liverpool, Sherrington Buildings, Liverpool, Merseyside L69 3GE, United Kingdom.
[email protected]
The importance of reactive metabolites in the pathogenesis of drug-induced toxicity has been a focus of research interest since pioneering investigations in the 1950s revealed the link between toxic metabolites and chemical carcinogenesis. There is now a great deal of evidence that shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, but how these toxic species initiate and propagate tissue damage is still poorly understood. This review summarizes the evidence for reactive metabolite formation from hepatotoxic drugs, such as acetaminophen,
tamoxifen, diclofenac, and troglitazone, and the current hypotheses of how this leads to liver injury. Several hepatic proteins can be modified by reactive metabolites, but this in general equates poorly with the extent of toxicity. Much more important may be the identification of the critical proteins modified by these toxic species and how this alters their function. It is also important to note that the toxicity of reactive metabolites may be mediated by noncovalent binding mechanisms, which may also have profound effects on normal liver physiology. Technological developments in the wake of the genomic revolution now provide unprecedented power to characterize and quantify covalent modification of individual target proteins and their functional consequences; such information should dramatically improve our understanding of drug-induced hepatotoxic reactions.
CYP17 polymorphism as a risk factor of tamoxifen-induced hepatic steatosis in breast cancer patients.
Ohnishi T, Ogawa Y, Saibara T, Nishioka A, Kariya S, Fukumoto M, Onishi S, Yoshida S.
Department of Tumor Radiology, Kochi Medical School, Oko-cho, Nankoku, Kochi 783-8505, Japan.
[email protected].
Oral administration of tamoxifen, an endocrine therapy for breast cancer, often induces hepatic steatosis (THS, tamoxifen-induced hepatic steatosis) as a complication, which can progress to non-alcoholic steatohepatitis (NASH). The development of this complication is strongly associated with three clinical risk factors; specifically, insulin resistance, central obesity, and hypertriglyceridemia, however a genetic predisposition to THS has yet to be investigated. The aim of this study is to determine whether genetic polymorphism of the P450c17alpha enzyme coded for by the CYP17 gene, responsible for regulating serum estrogen, has an association with THS. After obtaining informed consent from 180 eligible breast cancer patients treated with tamoxifen, DNA was collected and analyzed by restriction fragment length polymorphism assay and classified into alleles defined as A1 and A2. The absence or presence and extent of THS was evaluated by calculating the liver/spleen (L/S) ratio based on Hounsfield units with a CT scanner. Administration of tamoxifen led to THS (L/S ratio <0.9) in 57 (31.7%) of 180 patients while the remaining 123 (68.3%) patients did not develop THS. A significant difference in the distribution of CYP17 genotypes was observed between patients who developed THS and those who did not (P=0.021). A significantly higher frequency of the A2 allele was seen in the THS group (odds ratio, 1.90; 95% confidence interval, 1.21-2.99). Our study provides the first evidence that CYP17 polymorphism participates in the development of THS, and sheds light on the genetic causes of this side effect and genetic differences between tamoxifen-treated individuals.
And the following is another possible reason not to take it, but don't put too much stock in the study, it was done on post menopausal women:
Tamoxifen and megestrol acetate for postmenopausal breast cancer: diverging effects on liver proteins, androgens, and glucocorticoids.
Lofgren L, Wallberg B, Wilking N, Fornander T, Rutqvist LE, Carlstrom K, von Schoultz B, von Schoultz E.
Department of Surgery, St Gorans Hospital, SE-112 81 Stockholm, Sweden.
[email protected]
AIM: To compare the effects of tamoxifen and megestrol acetate on liver proteins, androgens, and glucocorticoids during adjuvant treatment for postmenopausal breast cancer. METHODS: A subgroup of women within a large prospective multicenter trial were followed with blood sampling every 3 mo during 2 yr. Women were randomized to receive either continuous tamoxifen 40 mg/d or repeated sequential treatment with tamoxifen and megestrol acetate (MA) 160 mg/d. RESULTS: We found profound and distinct differences between the two regimens. Tamoxifen increased steroid-binding proteins (SHBG and CBG) and suppressed circulating androgens and IGF-I. In contrast, the metabolic effects of tamoxifen were clearly antagonized by MA. There was a rise in IGF-I and marked suppression of steroid-binding proteins. Levels of free testosterone were reduced by 70%. MA also caused apparent adrenal suppression. CONCLUSION: The different effects on anabolic/catabolic balance and adrenal function may relate to certain clinical effects during treatment.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
Personally, this is my favorite DS product....abve and beyond anything.
