Hepatic system study

Sato et al. (1991) expanded their earlier PBPK model to account for differences in body weight, body fat content, and sex and applied it to predicting the effect of these factors on trichloroethylene metabolism and excretion. Their model consisted of seven compartments (lung, vessel rich tissue, vessel poor tissue, muscle, fat tissue, gastrointestinal system, and hepatic system) and made various assumptions about the metabolic pathways considered. First-order Michaelis-Menten kinetics were assumed for simplicity, and the first metabolic product was assumed to be chloral hydrate, which was then converted to TCA and trichloroethanol. Further assumptions were that metabolism was limited to the hepatic compartment and that tissue and organ volumes were related to body weight. The metabolic parameters, (the scaling constant for the maximum rate of metabolism) and (the Michaelis constant), were those determined for trichloroethylene in a study by Koizumi (1989) and are presented in Table 2-3. 

Our initial interest was in studying the disposition of phenol red in the shark. This turned out to be a good choice because nearly equal amounts of the model compound appeared in the urine and bile. After solving the body fluid collecting problems, we studied in greater depth, the transport properties of phenol red in both the renal and hepatic systems. 

Vinyl chloride has been associated with cancer in humans in a number of epidemiological studies. In four facilities engaged in the polymerization of vinyl chloride for at least 15 years, workers exposed for at least 5 years had a significant number of excess deaths due to malignant neoplasms (35 deaths observed, 23.5 expected). The excesses were found for four organ systems CNS (3 observed, 0.9 expected), respiratory system (12 observed, 7.7 expected) hepatic system (7 observed, 0.6 expected), and lymphatic and hematopoietic systems (4 observed, 2.5 expected). 

Special populations Use a starting dose of 6 mg/25 mg for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine/fluoxetine (eg, female gender, elderly, nonsmoking status). When indicated, perform dose escalation with caution in these patients. Olanzapine/fluoxetine has not been systemically studied in patients older than 65 years of age or in patients younger than 18 years of age. 

Kienhuis AS et al (2011) Application of toxi-cogenomics in hepatic systems toxicology for risk assessment acetaminophen as a case study. Toxicol Appl Pharmacol 250 96-107... 

Further toxicological studies with poly IC have shown it to be toxic to the vascular and hepatic systems of mice, dogs and rats, and on the endothelial cells of the small blood vessels of the chick cerebellum. ... 

EPA s review of recent epidemiologic studies of enviroiunental lead e q)0-sure and reproductive function concludes that there is strong evidence that increasing lead exposure is associated with reduced male fecundity or fertility, decreases in sperm count, and reduced sperm velocity and motility. EPA s draft report further concludes that deleterious associations with sperm count and quality are observed in occupationally exposed men who have mean BLLs as low as 20-45 pg/dL. EPA concluded that there was some association between maternal lead exposure and low birth weight toxicologic studies in animals have shown that lead exposme during early fetal development can result in abnormal retinal development and alterations in the developing hematopoietic and hepatic systems. 

Lead induces reproductive and developmental effects in laboratory rats after gestational or lactational exposure. Many of the effects occur in a concentration-dependent manner and have been observed at maternal BLLs that do not result in overt maternal toxicity (under 40 pg/dL). Animal studies have further demonstrated that effects of lead exposure during early development include impairment of retinal development and alterations in the developing hematopoietic and hepatic systems. Toxicology studies in male animals have reported de-... 

To monitor hepatic System A activity most investigations have used the model amino acid, 2-aminoisobutyric acid (AIB). Although AIB may show some uptake by System ASC in freshly isolated hepatocytes (10, 17), the majority of its Na -dependent transport in primary cultures of hepatocytes or in a variety of rat hepatoma cell lines is mediated by System A. AIB is not metabolized to a significant extent because of the lack of a hydrogen on the a carbon atom. This property along with its specificity, allows AIB to be used for in vivo studies as well as for prolonged incubations in vitro. 

Characterization of amino acid transport in eukaryotic cells has received a great deal of attention during the last decade and, for the reasons already mentioned, the liver has been a popular choice as a model tissue. As a result, more information has been obtained for amino acid transport in rat hepatocytes than for any other cell type with the possible exception of the Ehrlich ascites tumor cell. Furthermore, although nine separate systems have been shown to mediate amino acid transport in isolated hepatocytes. System A has been studied in greater detail than any of the others. Despite the large number of descriptive investigations that have focused on hepatic System A, there are several areas of characterization that remain to be explored. Some of these must wait until isolation of the protein(s) responsible for System A activity makes them feasible, but several interesting studies can be undertaken at the cellular level as well. 

Data from a single study in dogs suggest that hepatic first-pass metabolism may limit systemic availability of the parent compound following oral exposure (Braeckman et al. 1983). Placental transfer of methyl parathion was demonstrated in pregnant rats 1-3 days before parturition. Thirty minutes after administration, both methyl parathion and methyl paraoxon were found in fetal brain, liver, and muscle methyl parathion, but not methyl paraoxon, was detected in placenta and maternal liver (Ackermann and Engst 1970). Methyl parathion binds reversibly to serum albumin, but is readily distributed to the tissues (Braeckman et al. 1980, 1983). 

For hepatitis B and C, local production of antiviral cytokines at the site of infection, the liver, is expected to be better tolerated than systemic application. Studies... 

Methods of detection, metabolism, and pathophysiology of the brevetoxins, PbTx-2 and PbTx-3, are summarized. Infrared spectroscopy and innovative chromatographic techniques were examined as methods for detection and structural analysis. Toxicokinetic and metabolic studies for in vivo and in vitro systems demonstrated hepatic metabolism and biliary excretion. An in vivo model of brevetoxin intoxication was developed in conscious tethered rats. Intravenous administration of toxin resulted in a precipitous decrease in body temperature and respiratory rate, as well as signs suggesting central nervous system involvement. A polyclonal antiserum against the brevetoxin polyether backbone was prepared a radioimmunoassay was developed with a sub-nanogram detection limit. This antiserum, when administered prophylactically, protected rats against the toxic effects of brevetoxin. 

Ticlopidine inhibits the P2Yj2 platelet ADP receptor, thus inhibiting ADP-dependent activation of the GP Ilb/IIIa receptor. It has a slow onset of action and takes 3-7 days to reach its maximal antiplatelet effect. It is inactive in vitro and must undergo activation by the hepatic cytochrome p450 enzyme system. Secondary prevention trials have found that ticlopidine-treated patients have an estimated RRR of 33% for the composite endpoint of stroke, myocardial infarction, or vascular death after ischemic stroke. Significant adverse effects include bone marrow depression, rash, diarrhea, and thrombotic thrombocytopenic purpura. No clinical trials have studied ticlopidine for the treatment of stroke in the acute phase. 

Claims for acute hydrogen sulfide exposure that occurred over a 5-year period (1969-1973) in Alberta, Canada, primarily among petrochemical workers, were reviewed by Burnett et al. (1977). Acute effects noted included coma, disequilibrium, and respiratory insufficiency with pulmonary edema. Of 221 cases, there were 14 deaths. A follow-up study of 250 workers claims for hydrogen sulfide exposure from 1979 to 1983 in Alberta, Canada, found 7 fatalities that usually involved the central nervous and respiratory systems hepatic congestion and cardiac petechiae were also noted (Arnold et al. 1985). The difference in fatality rate (6% down to 2.8%) was attributed to improved first aid training and an increased awareness of the dangers of hydrogen sulfide. 

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