Hepatic microsomal enzymes stimulation

McCormack KM, Kluwe WM, Rickert DE, et al. 1978. Renal and hepatic microsomal enzyme stimulation and renal function following three months of dietary exposure to polybrominated biphenyls. Toxicol Appl Pharmacol 44 539-553. 

Table VI lists several drugs Inducing hepatic microsomal enzymes (5). These enzymes can metabolize the drug as well as other substrates. Barbiturates, grlseofulvln, and glutethlmlde Induce enzymes which metabolize coumarln and phenlndlone derivatives and thus reduce their anticoagulant activity. Dlphenylhydantoln and phenylbutazone stimulate cortisol hydroxylase activity and Increase the urinary excretion of B-hydroxy cortisol and decrease the concentration of cortisol In the plasma.

Long-term anticonvulsive therapy with diphenylhydantoin or phenobarbital is known to cause osteomalacia by influencing calcium metabolism (24,25). Alteration in the metabolism of vitamin D, presumably secondary to induction of hepatic microsomal enzymes, leads to the calcium and bone abnormalities (26). Patients on anticonvulsive therapy with phenytoin exhibit a decrease in serum 25-hydroxyvitamin D (27). Adequate dietary amounts of vitamin precursors or microsomal enzyme stimulators might prevent these effects of long-term therapy. 

The toxicity of dimethoate to mice may be increased by pre-treatment with phenobarbitone [58] or pentobarbitone [59], whereas the toxicities of phos-phamidon, dicrotophos and their Ai-dealkylated derivatives are decreased [58]. Dimethoate requires oxidative activation, yet the vinyl phosphates do not. In vitro studies confirm the induction of mouse hepatic microsomal enzymes by phenobarbitone pre-treatment, which activate schradan, mala-thion and parathion [60]. Microsomal induction by pre-treatment with pentobarbitone stimulates not only the activation of certain organophos-phates, but also their catabolism, thereby reducing their toxicity, for example mipafox [59]. 

Miranda, C.L. and R.S. Chhabra. 1980. Species differences in stimulation of intestinal and hepatic microsomal nixed-function oxidase enzymes. Biochem. Pharmacol. 29 1161-1165. 

Adaptive Enzyme Theory. The aliesterases are largely found in the microsomes of rat liver cells (44). Recently Hart and Fouts (51,52, 67-69) have presented evidence that in vivo administration of chlordan or chemically related DDT stimulates the activity of hepatic microsomal drug-metabolizing enzymes, as evidenced by proliferation of smooth-surfaced endoplasmic reticulum (SER) which was first noted with phenobarbital. Several reviews of hepatic drug metabolism... 

When healthy volunteers were exposed by inhalation to 100 or 400 ppm tetrahydrofuran in air, the percentage of expired tetrahydrofuran was 25-35%. The elimination half-life of tetrahydrofuran was 30 min in individuals exposed to 200 ppm for 3h. Some tetrahydrofuran is absorbed in the nasal cavity due to its solubility and inspiratory flow rate. Tetrahydrofuran uptake in the nasal tissue is dependent on its reaction with tissue substrates. Some tetrahydrofuran can be metabolized in the nasal cavity. Tetrahydrofuran blood concentrations were higher at 1 h postexposure than immediately after cessation of exposure. In vitro studies indicated that tetrahydrofuran was first hydroxylated by microsomal enzymes. High concentrations (lO molH ) of tetrahydrofuran inhibited the in vitro activity of rat hepatic cytochrome P450 by 80%. Tetrahydrofuran has been noted to enhance the toxic action of a number of compounds and stimulate the rapid absorption of reactive metabolites. Some of the tetrahydrofuran is excreted in the exhaled breath, while the various metabolites of tetrahydrofuran are excreted in the urine. 

The keto-imine (5) has been shown to be active in stimulating exocrine glands. Because purified porcine hepatic microsomal flavoprotein oxidase has been shown to oxidize slaframine to (5), this enzyme is postulated to be primarily responsible for activation of slaframine in vivo. ... 

A treatment of rutaecarpine causes an increase in renal microsomal enzymes related to CYPl A and enhances the activity and protein levels of CYPIA. It is known that caffeine is a mild stimulant. It is metabolized in the liver by CYPl A2, and it also has been shown to be an inducer of CYPl A2 in rodents on account of the increase in hepatic microsomal CYP1A2. Rutaecarpine is an inducer of cytochrome P450(CYP)1A in mouse liver and kidney. ... 

The toxic effects of synthetic polymers include inhibition of hepatic microsomal oxidase enzymes, stimulation of liver transaminases, hepatosplenomegaly, thymic involution, anaemia, and decrease in bone marrow cells Fortunately, many neutral synthetic polymers do not show toxic effects. For those polymers which exhibit toxic effects, e.g. polyanions, it is sometimes possible to separate the toxicity from antitumour, antiviral and immunological effects In general the toxicity of polyanions increases with molecular weight (particularly for M > 50,000). 

Acute parenteral administration of cadmium decreases hepatic microsomal cytochrome P-450 content and inhibits associated mixed-function oxidase enzyme activities (Hadley et al. 1974 Means et al. 1979 Gregus et al. 1982). Decreases in hepatic mixed function oxidase activities and cytochrome P-450 content have been demonstrated after chronic cadmium dosing for 6 months (Dudley et al. 1985). The reduction in cytochrome P-450 is due to increased heme degradation, which results from cadmium stimulation of heme oxygenase activity (Maines and Kappus 1977 Eaton et al. 1980). Such an effect would alter the capacity of an organism to adequately biotransform endogenous compounds as well as other xeno-biotics. In mitochondria, cadmium inhibits the transmembrane transport of calcium (Webb 1979) and oxidative phosphorylation (Sporn et al. 1969). 

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