Biochemical mechanisms in drug-induced liver injury:Certainties and doubts

Drug-induced liver injury is a significant and still unresolved clinical problem.Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development.Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites.Aging,preexisting liver disease,enzyme induction or inhibition,genetic variances,local O2 supply and,above all,the intrinsic molecular properties of the drug may affect this process.Necrotic death follows antioxidant consumption and oxidation of intracellular proteins,which determine increased permeability of mitochondrial membranes,loss of potential,decreased ATP synthesis,inhibition of Ca2+-dependent ATPase,reduced capability to sequester Ca2+ within mitochondria,and membrane bleb formation.Conversely,activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis.Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage.Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis,in which different HLA genotypes might play a major role.This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage.Future perspectives including new frontiers for research are discussed.

Therapeutic uses of animal biles in traditional Chinese medicine:An ethnopharmacological,biophysical chemical and medicinal review

Forty-four different animal biles obtained from both invertebrates and vertebrates(including human bile)have been used for centuries for a host of maladies in traditional Chinese medicine(TCM)beginning with dog,ox and common carp biles approximately in the Zhou dynasty(c.1046-256 BCE).Overall,different animal biles were prescribed principally for the treatment of liver,biliary,skin(including burns),gynecological and heart diseases,as well as diseases of the eyes,ears,nose,mouth and throat.We present an informed opinion of the clinical efficacy of the medicinal uses of the different animal biles based on their presently known principal chemical components which are mostly steroidal detergent-like molecules and the membrane lipids such as unesterified cholesterol and mixed phosphatidylcholines and sometimes sphingomyelin,as well as containing lipopigments derived from heme principally bilirubin glucuronides.All of the available information on the ethnopharmacological uses of biles in TCM were collated from the rich collection of ancient Chinese books on materia medica held in libraries in China and United States and the composition of various animal biles was based on rigorous separatory and advanced chemical identification techniques published since the mid-20th century collected via library(Harvard’s Countway Library)and electronic searches(PubMed and Google Scholar).Our analysis of ethnomedical data and information on biliary chemistry shows that specific bile salts,as well as the common bile pigment bilirubin and its glucuronides plus the minor components of bile such as vitamins A,D,E,K,as well as melatonin(N-acetyl-5-methoxytryptamine)are salutary in improving liver function,dissolving gallstones,inhibiting bacterial and viral multiplication,promoting cardiac chronotropsim,as well as exhibiting anti-inflammatory,anti-pyretic,anti-oxidant,sedative,anti-convulsive,anti-allergic,anti-congestive,anti-diabetic and anti-spasmodic effects.Pig,wild boar and human biles diluted with alcohol were shown to form an artificial skin for burns and wounds one thousand years ago in the Tang dynasty(618-907 CE).Although various animal biles exhibit several generic effects in common,a number of biles appear to be advantageous for specific therapeutic indications.We attempt to understand these effects based on the pharmacology of individual components of bile as well as attempting to identify a variety of future research needs.