Mixed-function oxidase activity, effect

Acrylonitrile alone has little tendency to produce duodenal ulcers in animals, but pretreatment with phenobarbital or Aroclor results in a marked increase in the incidence of such ulcers (Szabo et al. 1983, 1984). Although the mechanism of the ulcerogenic effect is not obvious, these data indicate that agents which enhanced mixed-function oxidase activity may also increase the toxicity of acrylonitrile. 

Arinc, E. and A. Sen. 1994. Effects of in vivo benzo[a]pyrene treatment on liver microsomal mixed-function oxidase activities of gilthead seabream (Sparus aurata). Comp. Biochem. Physiol. 107C 405-414. 

Robertson P, White EL, Bus JS. 1989. Effects of methyl ethyl ketone pretreatment on hepatic mixed-function oxidase activity and on in vivo metabolism of -hexane. Xenobiotica 19(7) 721-729. 

The possibility of interactions of ozone with other environmental stresses has received relatively little recent attention. Two exceptions are noteworthy, however reports of increased susceptibility to some of the actions of ozone in animals that are deficient in vitamin E or the converse (protection conferred by administration of vitamin E) and observations that exposure to ozone at less than 1.0 ppm reduces activity of the ( tochrome P-450 mixed-function oxidase activity of lungs. Although the implications of these observations are not yet clear, they remind us that nutritional variations or exposure to foreign chemicals that are metabolized by lung mixed-function oxidases may provide bases for unanticipated qualitative or quantitative effects associated with oxidant exposures. 

Several studies have been conducted to assess factors which influence the toxicity of hexachlorobutadiene. Most of these studies have involved effects of mixed function oxidase activity (MFO) on renal toxicity. The administration of MFO inhibitors including SKF-525A (Lock and Ishmael 1981) and piperonyl butoxide (Davis 1984 Hook et al. 1982) did not alter... 

The mechanism is believed to involve metabolic activation in the kidney itself. Thus, when radiolabelled chloroform was given to mice, in the kidney the radiolabel was localized in the tubular cells which were necrotic. Certain microsomal enzyme inducers such as 3-methylcholanthrene decreased the nephrotoxicity but not hepatotoxicity of chloroform, and phenobarbital pretreatment had no effect on nephrotoxicity but increased hepatotoxicity. Pretreatment with polybrominated biphenyls, however, increased toxicity to both target organs and also increased mixed function oxidase activity in both. In vitro studies have shown that microsomal enzymemediated metabolism of chloroform to C02 occurs in... 

Studies of the effects of typical inducers of mixed-function oxidase activity on DMN demethylation have also produced contradictory results. One group found that 3-methylcholanthrene and other PAH inhibited rat hepatic DMN demethylase activity (and DMN carcinogenicity) (474, 476), while others observed an increase in activity (136, 331, 374). Similar results were obtained in studies with Aroclor 1254, which was shown by one group to induce DMN demethylase activity in mouse liver (90), while other investigators found no change in activity (14). Contradictory results were also observed with phenobarbital (10, 13, 331, 374). These contradictions appear to have been at least partially resolved by the discovery of two hepatic forms of DMN demethylase. These two forms of DMN demethylase appear to respond differently to pretreatment with typical enzyme inducers one form is induced and the other repressed (11). The two different forms catalyze DMN demethylation at low substrate concentrations (0-4 mM)... 

DMN demethylase activity was repressed by pretreatment with a number of substances other than those discussed above. These include benzo[a]pyrene and numerous other PAH (72), /3-naphthoflavone (70), pregnenolone-16a-carbonitrile (70), aminoacetonitrile (70), cysteine (727, 547), nitrososarcosine (759), diethylnitrosamine (759), dibutylnitrosamine (759), dibenamine (445), and glucose (475). Other pretreatments including ethanol, isopropanol, acetone, L-tiyptophan, and casein increased DMN demethylase activity (727, 527, 450, 457, 476). The repression of DMN demethylase by substances which are often inducers of mixed-function oxidase activity is unusual although not unprecedented. These effects require further study since changes in DMN metabolism frequently result in altered toxicity or carcinogenicity. The complex pattern of induction and repression of DMN demethylase activity suggests that there are multiple forms of this enzyme. 

Pipe RK, Moore MN (1986) An ultrastructural study on the effects of phenanthrene on lysosomal membranes and distribution of the lysosomal enzyme 8-glucuronidase in digestive cells of the periwinkle Littorina littorea. Aquat Toxicol 8 65-76 Plesha PD, Stein JE, Schiewe MH, McCain BB, Varanasi U (1988) Toxicity of marine sediments supplemented with mixtures of selected chlorinated and aromatic hydrocarbons to the infaunal amphipod Rhepoxynius abronius. Mar Env Res 25 85-97 Pohl RJ, Bend JR, Guarino AM, Fonts JR (1974) Hepatic microsomal mixed-function oxidase activity of several marine species from coastal Maine. Drug Metab Disp 2 545-555 Post S, Wells MR (1985) Metabolism of aldrin by the freshwater planarian Phagocata gracilis. Bull Environ Contam Toxicol 34 871-875... 

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). 

Mehendale HM, Chen PF, Fishbein L, et al. 1973. Effect of mirex on the activities of various rat hepatic mixed-function oxidases. Arch Environ Contam Toxicol 1(3) 245-254. 

An effect of ozone on lung microsomes has been suggested by morpholine studies that indicated alterations in the endoplasmic reticulum, Biochemical evidence of an effect on microsomal enzymes was originally obtained in the studies of Palmer et who demonstrated that ozone exposure (0.75-10 ppm for 3 h) resulted in a decrease in activity of Syrian hamster lung benzopyrene hydroxylase, a mixed-function oxidase that depends on cytochrome P-450. No changes in hepatic activities of this enzyme were observed, and the results were similar in animals in which high activities of benzopyrene hydroxylase had been induced. The maximal effect was not observed until a few days after the single ozone exposure. Palmer et also reported a decrease in rabbit tracheobronchial mucosal benzopyrene hydroxylase activity after exposure to similar ozone concentrations. 

Kerklaan, P.R.M.. Bouter, S., Zijlstra, J. A. Mohn, GR. (1986) The effect of mixed-function oxidase and amine oxidase inhibitors on the activation of dialkylnitrosamines and 1,2-dimethylhydrazine to bacterial mutagens in mice. J. Cancer Res. din. Oncol., Ill, 196-202... 

Cyclophosphamide in its parent form does not have direct cytotoxic effects, and it must be activated to cytotoxic forms by microsomal enzymes (Figure 55-5). The liver microsomal cytochrome P450 mixed-function oxidase system converts cyclophosphamide to 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide. These active metabolites are believed to be delivered by the bloodstream to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms—phosphoramide mustard and acrolein—occurs. The liver appears to be protected through the enzymatic formation of the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide. 

Pond et al (23) reported that the rate of metabolism of tolbutamide was decreased by chronic adminstration of certain drugs, they claimed that the tolbutamide half-life was increased by chronic adminstration of sulphaphenazole (9.5 hrs to 28.6 hrs), phenylbutazone (7.9 hrs to 23.1 hrs), and oxyphenbutazone (8.1 hrs to 30.2 hrs). The rate of elimination of tolbutamide was decreased within one to two hours after a single dose of sulphaphenazole and the half-life was increased from 9.2 hrs to 25.7 hrs. In contrast, phenylbutazone and oxyphenbutazone, adminstered as a single dose 800 mg have no immediate effect on tolbutamide elimination. It is suggested that phenylbutazone and oxyphenbutazone act by inducing a form of a cytochrome P-450 with low activity for tolbutamide hydroxylation, whereare, sulphaphenazole acts by direct inhibition of the microsomol mixed function oxidase system. 

---