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When I got my liver function test, they also included a protein level test which shows I am low in that department (I'm a dairy-only vegetarian).
My doctor was very interested in this, because the medication binds to proteins and that's how it leaves the body. He said the deficiency may be the reason I get toxic reactions from almost everything I take, including dental anethetics.
So, the plan: I bought a really good blender and lots of protein shakes, and I hope to have 3 shakes a day (with additional food) and bring my protein level up. Hopefully this will cut toxicity and side effects for me.
I thought it was really fascinating to find this out since I've been so sensitive for so long. I can't believe no one ever noticed my protein levels were low before
Nuts are very healthy to eat and are high in protein. I use organic peanut butter which I've skimmed the oil off of for part of my protein total.
I'm also eating a lentil pilaf made by Near East which is really good and has lots of protein.
I agree, there should be some way of warning people about low protein levels and medication toxicity. I just lucked out having a *wonderful* psychiatrist that thinks outside the box.
A little off the track is an excellent article on how genes can cause drug side effects....Pharmacogeneticsie "Women often respond differently than men to drugs at the same dose levels. For example, women are more likely to have a good response to the antidepressant drugs that act as serotonin specific reuptake inhibitors (SSRIs, the group that includes Prozac and Paxil) than they are to the older group of tricyclic antidepressants .""Women may show a greater response to some steroid hormones than men do, but have a lower level of response to some anti-anxiety medications than men.""Since many drugs are soluble in body fat, people with large amounts of fat will have these drug deposited into their fat stores. This means that there are lower levels of the drug that can reach the actual organs on which they work. " It is definitely a worthwhile article to read.
Neurology 2003 Apr 8;60(7):1125-9 :
Effect of L-dopa on plasma homocysteine in PD patients: relationship to B-vitamin status.
Miller JW, Selhub J, Nadeau MR, Thomas CA, Feldman RG, Wolf PA.
Vitamin Bioavailability Lab, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA.
jwmiller@ucdavis.edu
BACKGROUND: The antiparkinsonian drug L-dopa causes increased cellular synthesis of homocysteine and consequent hyperhomocysteinemia in rats. This effect of L-dopa on plasma homocysteine is accentuated under conditions of impaired homocysteine metabolism such as folate deficiency. OBJECTIVE: To investigate the effect of L-dopa administration and B-vitamin status on plasma homocysteine concentrations in humans with PD. METHODS: Plasma homocysteine, folate, vitamin B(12), and pyridoxal-5'-phosphate (PLP) concentrations were determined in 40 individuals diagnosed with idiopathic PD who were being treated as outpatients at the Boston University Medical Center Neurology Clinic. Twenty of the patients were on L-dopa therapy (treatment group) and 20 were L-dopa-naive (control group). RESULTS: The mean plasma homocysteine concentration was higher in the treatment group than in the controls (p = 0.018). Plasma homocysteine was correlated with plasma folate, vitamin B(12), and PLP concentrations in the treatment group (p
Karabiber H, Sonmezgoz E, Ozerol E, Yakinci C, Otlu B, Yologlu S.
Kahramanmaras Sutcuimam Universitesi, Tip Fakultesi, Pediatri Anabilim Daly 46050, Kahramanmaras, Turkey.
hkarabiber@hotmail.com
Homocysteine (HMC) is a sulfur containing amino acid, which plays a role in methionine metabolism. Folic acid (FA) and vitamin B12 (B12) are essential for remethylization of HMC to methionine. HMC level increases in the deficiency of these vitamins. Hyperhomocysteinemia causes vascular endothelial damage, which causes atherosclerosis. The aim of this study is to investigate the effect of valproate (VA) and carbamazepine (CBZ) on the serum levels of HMC, B12, and FA.Thirty-six children receiving CBZ and 30 children receiving VA for epilepsy for the last 1-year period and 29 healthy children as control were the population of this study. After 6 h of fasting serum HMC, B12, and FA levels were measured and results were compared statistically.Mean values of HMC, FA, and B12 levels in control group were 9.2+/-2.7 micromol/l, 9.0+/-2.0 ng/ml, and 342+/-162 pg/ml, in VA group 14.0+/-6.8 micromol/l, 7.3+/-2.9 ng/ml, and 368+/-159 pg/ml, in CBZ group 16.0+/-13.1 micromol/l, 7.5+/-3.3 ng/ml, and 285+/-158 pg/ml, respectively. Serum HMC levels were higher in VA and CBZ groups than control group (P<0.01 and P<0.05, respectively). Serum FA levels were lower in VA and CBZ groups compared to control group (P<0.05). Serum levels of B12 were not different between VA and control groups (P>0.05). In CBZ group serum B12 levels were lower than control group (P<0.05).FA may be added to the treatment protocol (if the patients take only CBZ, then B12 should also be added) for patients taking these antiepileptic drugs to decrease the degenerative effect of VA and CBZ on vascular endotheliumJ Neuropsychiatry Clin Neurosci 2003 Winter;15(1):64-6 :
Low serum folate levels as a risk factor for depressive mood in patients with chronic epilepsy.
Rosche J, Uhlmann C, Froscher W.
Department of Neurology and Epileptology, University of Ulm, Ravensburg, Germany.
This study takes into consideration whether low serum folate levels may contribute to depressive mood in patients with chronic epilepsy. The serum folate levels and the score on the Self-Rating Depression Scale (SDS) were examined in 46 patients with chronic epilepsy. Patients with a score indicating at least minor depression on the SDS had a significantly lower serum folate level than patients with a normal score on SDS. There was a significant negative correlation between the serum folate levels and the SDS score. A serum folate level below 7.5 ng/ml was significantly associated with a pathological score on SDS. Because a serum folate level of 7.5 ng/ml is in the normal range for many laboratories, further studies using total plasma homocysteine as a sensitive measure of functional folate deficiency are required to elucidate the impact of folate metabolism on depressive mood in patients with chronic epilepsy. J Nutr 2002 Sep;132(9):2737-42 :
Acute valproate administration impairs methionine metabolism in rats.
Ubeda N, Alonso-Aperte E, Varela-Moreiras G.
Seccion de Nutricion, Bromatologia y Dietetica, Facultad de Ciencias Experimentales y de la Salud, Universidad San Pablo CEU, Madrid, Spain.
nubeda@ceu.es
Valproate (VPA) is a drug widely used to treat epilepsy, but it has serious adverse effects including hepatotoxicity, teratogenicity and antifolate activity. The mechanism underlying VPA toxicity is unclear although an interaction with folate and other metabolites involved in methionine metabolism has been suggested. The present study was undertaken to evaluate potential changes in the metabolic function of the methionine cycle after acute exposure to a single dose of valproate. Female Wistar rats (n = 30) were treated with 400 mg/kg of VPA. Different groups of six rats were killed at 1 (t1), 3 (t3), 6 (t6), 9 (t9), and 24 (t24) hours after the injection. One group of rats was untreated (n = 6) and was considered the control group. The most pronounced effects of VPA administration were observed 1 h after drug injection. VPA induced a 56% reduction in methionine adenosyltransferase activity and a 54% reduction in plasma vitamin B-6. Increases in the hepatic concentration of S-adenosylhomocysteine and oxidized glutathione, and a reduction in the S-adenosylmethionine/S-adenosylhomocysteine transmethylation ratio also occurred at 1 h. All of these alterations, however, were normalized within 24 h, parallel with a decrease in serum VPA concentration. The acute effects of VPA suggest that the alterations in the methionine cycle could be the common mechanism underlying the hepatotoxic, teratogenic and antifolate effects of the drug.
J Nutr 2002 Aug;132(8 Suppl):2336S-2339S :
The effects of diet, genetics and chemicals on toxicity and aberrant DNA methylation: an introduction.
Poirier LA.
National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079, USA.
lpoirier@nctr.fda.gov
In the early 1930s, the group of Banting and Best showed that the choline moiety of lecithin was responsible for the prevention of the fatty livers produced in pancreatectomized dogs treated with insulin. This was the first study linking abnormal methyl metabolism with disease. Since then, deficiencies of each of the four essential dietary sources of methyl groups (choline, methionine, vitamin B-12 and folic acid) have been associated with increased risk of a number of diseases. Choline-deficient diets were shown to enhance liver tumor formation in rats, and such diets frequently were found to lead to atherosclerosis. Although methionine deficiency per se was not extensively studied in vivo, its metabolic antagonist ethionine did cause liver cancer and pancreatic toxicity in rodents. Deficiencies of vitamin B-12 and of folic acid have long been shown to cause neurological disturbances and birth defects both in humans and in experimental animals. In 1969 inborn errors of metabolism leading to the accumulation of the demethylated metabolite of methionine, homocysteine, were proposed as contributing to the early onset of atherosclerosis. Before 1990, numerous studies described the abnormal methylation of DNA in tumors and transformed cells. Less frequently investigated, however, were the exogenous and endogenous agents leading to such abnormal methylation. These included genetic variants among rodent strains and the methyl-deficient diets that caused liver cancer. In addition, several chemicals, particularly carcinogens, were shown to alter DNA methylation. The possible links between chemically induced alterations in DNA methylation and development of other diseases were little explored. However, by 1990, a chain of causality had been established in experimental carcinogenesis linking dietary methyl deficiency with methyl insufficiency in vivo, as well as with the abnormal methylation of DNA and of specific genes. Also during this period, the diminished activity of the enzyme methylenetetrahydrofolate reductase (EC 1.5.1.20), which is responsible for the actual de novo synthesis of methyl groups, was shown to be associated with increased risk of developing atherosclerosis, neurological disorders and birth defects. The exponential rise in studies on methyl metabolism and DNA methylation since then enables us to examine here the extent to which the mechanisms by which abnormal methylation processes seem to exert their toxic effects in one disease may be applicable to other pathologies.
J Environ Pathol Toxicol Oncol 1998;17(1):75-80 :
Restoration of methylmercury inhibited adenosine triphosphatases during vitamin and monothiol therapy.
Bapu C, Rao PA, Sood PP.
Department of Toxicology, B.V. Patel PERD Centre, Thaltej, Ahmedabad, India.
The aim of our investigation was to examine the efficacy of monothiols and vitamins in the restoration of ion-dependent ATPases in mice intoxicated with methylmercury chloride (MMC). A daily dose of glutathione (GSH), N-acetyl-DL-homocysteine thiolactone (NAHT), vitamin B complex, or vitamin E, either alone or in combination, resulted in significant recovery of N+, K+, Mg++ ATPases. A significant recovery was noted in some therapeutic groups. As the therapeutic agents used in this study are natural physiological components present in all the animals, they are unlikely to be injurious if applied in appropriate doses. Hence, they can be safely recommended for methylmercury detoxication.
Curr Opin Drug Discov Devel 2003 Jan;6(1):81-91 :
Disease-related determinants of susceptibility to drug-induced idiosyncratic hepatotoxicity.
Boelsterli UA.
HepaTox Consulting, PO Box 14, CH-4148 Pfeffingen, Switzerland.
boelsterli@hepatox.ch
Idiosyncratic adverse drug reactions, including unpredictable hepatotoxicity, remain a serious challenge in drug development. Besides patient-specific susceptibility factors (genetic and/or acquired), determinants of the underlying disease may also predispose the patient to a drug's potential toxicity. Examples include viral infections, inflammatory conditions, neurodegenerative diseases and type II diabetes. This review focuses on diseases (therapeutic indications) often associated with mitochondrial abnormalities, and which are treated with drugs mechanistically linked to potential mitochondrial toxicity, thus superimposing these mitochondrial events. The need for an increased use of animal models of human disease in mechanistic investigations and drug candidate selection will also be emphasized.
Curr Drug Metab 2002 Aug;3(4):367-77 :
Mechanism of idiosyncratic drug reactions: reactive metabolite formation, protein binding and the regulation of the immune system.
Ju C, Uetrecht JP.
Molecular and Cellular Toxicology Section, Laboratory of Molecular Immunology, NHLBI, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
JuC@NHLBI.NIH.GOV
Drug-induced adverse reactions, especially type B reactions, represent a major clinical problem. They also impart a significant degree of uncertainty into drug development because they are often not detected until the drug has been released onto the market. Type B reactions are also termed idiosyncratic drug reactions by many investigators due to their unpredictable nature and our lack of understanding of the mechanisms involved. It is currently believed that the majority of these reactions are immune-mediated and are caused by immunogenic conjugates formed from the reaction of a reactive metabolite of a drug with cellular proteins. It has been shown that most drugs associated with idiosyncratic reactions form reactive metabolites to some degree. Covalent binding of reactive metabolites to cellular proteins has also been shown in many cases. However, studies to reveal the role of reactive metabolites and their protein-adducts in the mechanism of drug-induced idiosyncratic reactions are lacking. This review will focus on our current understanding and speculative views on how a reactive metabolite of a drug might ultimately lead to immune-mediated toxicity.
Z Gastroenterol 2002 May;40(5):305-26 :
[Drug-induced liver diseases]
[Article in German]
Teschke R.
Medizinische Klinik II, Klinikum Stadt Hanau, Akademisches Lehrkrankenhaus der Johann Wolfgang Goethe-Universitat Frankfurt/Main, Germany.
About 1000 drugs produced world-wide may lead to clinically relevant hepatotoxic reactions which are unpredictable at normal doses and occur at various frequencies. Among these are well established therapeutic drugs which have been in use for years or decades as well as newly introduced drugs, the number of which is steadily increasing. For the development of drug-induced liver disease, various pathogenetic mechanisms, many risk factors and variable latency periods are known. The histological picture may imitate practically all known non-toxic liver diseases from which toxic liver disease needs to be differentiated. Patients under drug therapy require regular medical follow-up with regard to the development of toxic liver disease since the prognosis is only good with early recognition and immediate withdrawal of the alleged drug. Specific therapeutic modalities to prevent toxic liver disease are limited to paracetamol overdosage which is treated by the application of N-acetylcysteine. For other drug-induced liver diseases characterised by a prolonged course, therapy with ursodeoxycholic acid or steroids may be helpful. When fulminant drug-induced liver failure occurs, liver transplantation is the therapy of choice with a better prognosis than a conventional therapy. Despite this therapeutic option more than 40 different drugs are known to have caused lethal forms of toxic liver disease. Physicians have therefore to be alert to early recognize drug-induced liver disease and to withdraw the drug at first suspicion of the diagnosis.
Semin Liver Dis 2002;22(2):145-55:
Epidemiology and individual susceptibility to adverse drug reactions affecting the liver.
Larrey D.
Service d'hepato-gastroenterologie et transplantation, Hopital Saint Eloi, Montpellier, France. d-larry@chu-montpellier.fr
Adverse drug reactions affecting the liver represent an important challenge for safety in drug development. Drugs can reproduce practically the whole spectrum of liver diseases, but acute hepatitis is the most common syndrome. Drug hepatotoxicity is one of the most common causes of fulminant hepatitis. Most hepatic drug reactions occur in only a small proportion of individuals, making them difficult to detect at the time of drug development. Liver injury is principally recognized on the basis of spontaneous reports within the first 2 years of marketing a new drug. The prevalence of drug hepatotoxicity is poorly documented by a small number of retrospective studies. Despite the development of international analytical methods to allow standardized evaluation, the diagnosis remains indeterminate in many cases. Acquired and genetic factors influence the individual susceptibility to drug hepatotoxicity. Important directions for the future include prospective studies of the incidence of hepatic adverse drug reactions, finding specific markers that augment or replace causality assessment, and further elucidating the role of the genetic and environmental factors that contribute to individual susceptibility
Toxicology 2001 Feb 2;158(1-2):11-23:
Metabolic activation in drug allergies.
Park BK, Naisbitt DJ, Gordon SF, Kitteringham NR, Pirmohamed M.
Department of Pharmacology and Therapeutics, University of Liverpool, PO Box 147, L69 3GE, Liverpool, UK.
bkpark@liverpool.ac.uk
Drug allergies are a major problem in the clinic and during drug development. At the present time, it is not possible to predict the potential of a new chemical entity to produce an allergic reaction (hypersensitivity) in patients in preclinical development. Such adverse reactions, because of their idiosyncratic nature, only become apparent once the drug has been licensed. Our present chemical understanding of drug hypersensitivity is based on the hapten hypothesis, in which covalent binding of the drug (metabolite) plays a central role in drug immunogenicity and antigenicity. If this theory is correct, then it should be possible to develop in vitro systems to assess the potential of drugs to bind to critical proteins, either directly or indirectly after metabolic activation to protein-reactive metabolites (bioactivation) and initiate hypersensitivity. The purpose of this review is to assess critically the evidence to support the hapten mechanism, and also to consider alternative mechanisms by which drugs cause idiosyncratic toxicity.
Toxicol Lett 2003 Mar 20;139(1):45-54:
Inhibition of nitrosodiethylamine-induced hepatocarcinogenesis by dietary turmeric in rats.
Thapliyal R, Naresh KN, Rao KV, Maru GB.
Carcinogenesis Division, Cancer Research Institute, Tata Memorial Center, Parel, Mumbai 400 012, India
Turmeric, widely used in food and medicine has been shown to prevent benzo(a)pyrene [B(a)P] or dimethylbenz(a)anthracene (DMBA)-induced forestomach, skin and mammary tumors in mice and/or rats. In this study we examine the modulatory effects of turmeric on nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in rats. Female Wistar rats were administered NDEA (200 ppm) through drinking water (5 days per week) for 4 weeks. Control and/or NDEA-treated rats received 0, 0.2, 1.0 or 5.0% turmeric diet (w/w) either before (2 weeks), during (4 weeks) and after NDEA exposure (10 weeks) or starting from 24 h after NDEA exposure for 10 weeks. NDEA-treated rats receiving 1 or 5% turmeric before, during and after carcinogen exposure showed significant decrease in number of gamma glutamyl transpeptidase (GGT) positive foci measuring >500 or >1000 microm and decrease in the incidence of NDEA-induced focal dysplasia (FD) and hepatocellularcarcinomas. Decrease in the number of GGT positive foci measuring >1000 microm was also observed in NDEA-treated rats receiving 0.2% turmeric, although no decrease in tumor incidence was noted. On the other hand, similar levels of turmeric treatment (0.2, 1 and 5%) after exposure to NDEA did not show any protective effects. The underlying mechanism(s) of chemoprevention of NDEA-induced hepatocarcinogenesis need to be explored
Life Sci 2003 Feb 21;72(14):1563-71 :
The collagenolytic effects of the traditional Chinese medicine preparation, Han-Dan-Gan-Le, contribute to reversal of chemical-induced liver fibrosis in rats.
Li C, Luo J, Li L, Cheng M, Huang N, Liu J, Waalkes MP.
Department of Pharmacology, Guiyang Medical College, China.
li8@niehs.nih.gov
Han-Dan-Gan-Le (HDGL), a Chinese herb preparation composed of Stephaniat tetrandra, Salvia miltorrhiza, Radix paeoniae, Astragalus membranaceus, and Ginkgo biloba, has been used to treat human liver fibrosis. This study was designed to examine the therapeutic effect of HDGL on chemical-induced liver fibrosis in adult Wistar rats. Liver fibrosis was produced in rats by carbon tetrachloride (1.2 ml CCl(4)/kg, 2 times/week, after an initial dose of 5.0 ml CCl(4)/kg, sc), plus a diet of 20% fat, 0.05% cholesterol (continuous) and 30% alcohol in the drinking water ad libitum (every other day) for 8 weeks. HDGL (0.5 and 1.0 g/kg, ig, daily for 6 weeks) was administered to rats 72 hrs after the last dose of CCl(4) to examine its therapeutic effects on chemical-induced liver fibrosis. Upon pathological examination, the HDGL treatment had significantly reversed chemical-induced liver fibrosis and other hepatic lesions. Hepatic collagen accumulation induced by CCl(4) was markedly reduced by HDGL treatment, as evidenced by hepatic collagen content and by immunohistochemical analysis of type-I collagen in liver. HDGL appeared to stimulate the collagenolytic process in the liver, as a 30-50% increase in urinary excretion of hydroxyproline was observed with HDGL treatment as compared to rats only given CCl(4). In conclusion, HDGL can effectively reverse chemically induced liver fibrosis, and this appears to be due, at least in part, to the stimulation of hepatic collagenolysis, resulting in a resolution of hepatic fibrosis.
Life Sci 2003 Jan 17;72(9):1061-71 :
Protection of tea melanin on hydrazine-induced liver injury.
Hung YC, Sava VM, Blagodarsky VA, Hong MY, Huang GS.
Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, China Medical College, 91 Hsueh Shih Road, Taichung 404, Taiwan, ROC.
The protective activity of melanin derived from tea (MDFT) was studied using hydrazine as a DNA-reactive chemical agent. Intra-peritoneal administration of MDFT at the doses of 5 or 20 mg/kg dose-dependently prevented liver toxicity induced by hydrazine in rats. It normalized rises in serum alanine transferase activity and a decrease in the glutathione level in the liver. It also reduced the hepatic malondialdehyde concentration. Monitoring the intensity of chemiluminescence showed that MDFT could prevent the production of free radicals that are generated owing to metabolic transformation of hydrazine. It also prevented the formation 8-hydroxy-deoxyguanosine (8-OH-dG) DNA adducts. The results obtained in vivo and in vitro suggest that MDFT confers marked protection of the liver against hydrazine-induced oxidative toxicity.
Biol Pharm Bull 2002 Nov;25(11):1451-5 :
Saeng-Maek-San, a medicinal herb complex, protects liver cell damage induced by alcohol.
Park KJ, Lee MJ, Kang H, Kim KS, Lee SH, Cho I, Lee HH.
Department of Biological Sciences, Konkuk University, Seoul, Korea.
kkupkj@chol.net
The effect of treatment with Saeng-Maek-San (SMS) Complex (SMS1 or SMS2) upon rat hepatocytes exposed to alcohol was investigated. We compared the serum biochemistry and liver histology of rats administered both alcohol and SMS to control rats treated with alcohol alone. SMS treatment resulted in a significant reduction in the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and triglycerides (TG) compared to the control rats. In contrast, expression levels of alcohol dehydrogenase (ADH) were increased. Electron microscopy indicated that administration of SMS preserved the structure of organelles, including the nucleus and mitochondria. In addition, lipid droplets and secondary lysosomes were observed in the control rats. These data suggest that SMS represents an excellent candidate for protection of rat hepatocytes from alcohol-mediated damage
Curr Opin Pediatr 2002 Oct;14(5):601-7 :
Drugs and the liver: advances in metabolism, toxicity, and therapeutics.
Buratti S, Lavine JE.
Division of Pediatric Gastroenterology and Nutrition, University of California, San Diego and Children's Hospital and Health Center, 92103-8450, USA.
Biotransformation of drugs is one of the major functions of liver. Hepatic drug metabolism develops early in organogenesis and continues in postnatal life through puberty. Genetic and developmental studies on hepatic drug metabolism show that immaturity, polymorphisms, and altered balance of different hepatic enzymatic activities affect pharmacologic inactivation and alter the risk of toxic effects of drugs on the hepatic parenchyma. Although drug-induced liver disease is less common in children, several reports of hepatotoxicity are published every year. Furthermore, the increasing use of nonregulated remedies (eg, herbal preparations or recreational drugs) increases the risk of unpredictable and potentially severe reactions. Many significant advances in the treatment of hepatic diseases have been achieved recently. However, differences in clinical features, natural history, and response to treatment between children and adults require evaluation of new therapeutic options in focused pediatric clinical trials.