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PubMed1989

The hepatic microsomal mixed-function oxygenase (MFO) system of Alligator mississippiensis: induction by 3-methylcholanthrene (MC).

1. Pretreatment of alligators i.p. with 3-methylcholanthrene (MC) resulted in a 1.6-fold increase (P less than 0.001) in cytochrome P-450 specific content and a bathochromic shift in the absorption maximum of reduced, CO-liganded microsomes (448 nm). 2. Control and MC microsomal cytochrome P-450 binding spectra with a number of type I and type II ligands were similar. 3. MC treatment of alligators resulted in a 12-fold increase in benzo[a]pyrene hydroxylase activity, which was inhibited 82% by 0.1 mM alpha-naphthoflavone. The turnover number (units/nmol P-450) of aminopyrine N-demethylase and 7-ethoxycoumarin O-deethylase were unaffected by MC treatment. 4. The O-dealkylation (OD) of a series of alkoxyresorufins (ethoxyresorufin (ER), methoxyresorufin (MR), benzyloxyresorufin (BR), and pentoxyresorufin (PR] was investigated. MC treatment resulted in a significant (P less than 0.001) increase in turnover number of EROD, MROD, and BROD over control values. The turnover number of PROD was unaltered by MC treatment. 5. Western blots showed that control alligator microsomes contain a protein band of lower mol. wt. than either rat cytochrome P-450c (P450 IA1) or P-450d (P450 IA2), which was recognized by antibodies to both P-450c and P-450d but preferentially by that against P-450c. This protein band was induced 3-4-fold by MC. MC treatment induced a second protein band in alligator microsomes of the same mol. wt. as rat P-450d, recognized preferentially by antibodies to rat cytochrome P-450d. 6. These results illustrate that the alligator mixed-function oxidase (MFO) system responds to MC in a similar manner as described in mammals, i.e. induction in P-450 content, increases in specific MFO activities, and the apparent expression of different P-450 isoenzymes.

Alligators and Crocodiles↗
PubMed2004

Comparison of liver mixed-function oxygenase and antioxidant enzymes in vertebrates.

We performed a comparative analysis of cytochrome P450, cytochrome b5, MFO associated enzymes and cytosolic antioxidant enzymes in hepatic microsomes and cytosolic fractions prepared from five animal species representing three vertebrate classes living in tropical conditions (Brazil). The data obtained show that rats have higher hepato-somatic index, specific cytochrome b5 concentration, and NADPH-dependent cytochrome c (P450) activity compared to ectothermic species, SOD activity similar to those in amphibians, and specific concentration of cytochrome P450 and catalase activity lower than in a toad, but higher than in fishes and a frog. Our data indicate that tropical fishes may have reduced xenobiotic-metabolizing ability compared to the rat and amphibians. In contrast to fish and rat, amphibians have a low ratio (< 0.5) of cytochrome b5 concentration to that of P450. Most species showed cytochrome b5 sensitivity to oxygen. Thus, the use of sodium dithionate as a reducer, rather than NADPH, may be preferential in b5 determinations.

Animals↗
PubMed1976

Activation of 3':5'-cyclic AMP-dependent protein kinase and induction of ornithine decarboxylase as early events in induction of mixed-function oxygenases.

The parenteral administration of a single dose of 3-methylcholanthrene to rats caused an increase in the liver of the concentration of 3', 5'-cAMP and of the activity of cAMP-dependent protein kinase (ATP:protein phosphotransferase, EC 2.7.1.37). These events were followed by an increased activity of ornithine decarboxylase (L-ornithine carboxy-lase, EC 4.1.1.17), the enzyme that controls the biosynthesis of polyamines. Finally, the activity of benzo[a]pyrene hydroxylase, as well as the amount of cytochrome P-448, was increased. Similarly, after the administration of phenobarbital, there was first an increase in the cAMP concentration and in the activity of cAMP-dependent protein kinase, then the induction of ornithine decarboxylase, and finally, an enhanced activity of ethylmorphine N-demethylase and an increased content of cytochrome P-450. These data suggest that the drug-induced processes in liver that increase the activities of the oxidative, and presumably other, drug-metabolizing enzymes include the following sequence of events: (1) increase in cAMP concentration and/or activation of cAMP-dependent protein kinase; (2) induction of ornithine decarboxylase; and, (3) induction of drug-metabolizing enzymes.

Animals↗
PubMed1987

Effect of haem arginate therapy on porphyrin metabolism and mixed function oxygenase activity in acute hepatic porphyria.

The effect of haem arginate on porphyrin metabolism and haemoprotein function was studied during seven attacks of acute hepatic porphyria in 5 patients. In each attack it greatly reduced the overproduction of porphyrin precursors and repressed the overactivity of the rate-controlling enzyme of haem synthesis delta-aminolaevulinic acid (ALA) synthase measured in leucocytes. Antipyrine clearance, an index of the oxidative function of cytochromes P-450, the major group of hepatic haemoproteins, was increased during haem therapy. Thus, haem arginate not only suppresses the overproduction of haem precursors but also improves hepatic oxidative metabolism in acute porphyria.

Acute Disease↗
PubMed1987

A test using cultured cells with induced mixed-function oxygenase in the unscheduled DNA synthesis assay for detecting promutagens/procarcinogens.

The human FL cell line contains very low levels of constitutive AHH activity, but it could be greatly induced by NE, beta-NF and 3-MC, and induced slightly by PB. When two different types of inducer, for example, 3-MC and PB or 3-MC and NE were given in combination, an additive inductive effect was not observed. Both the constitutive and induced AHH in FL cells have characteristics of MFO, namely, NADPH-dependence and CO-sensitivity. The fact that the constitutive and induced AHH in FL cells could be inhibited by a known hydroxylase inhibitor 7,8-BF indicated that the AHH in FL cells belongs to the cytochrome P-448 dependent MFO type. After removal of inducer from the medium, the induced AHH activity remained at a high level for at least 24-36 h. By using AHH-induced FL cells in the UDS assay system for the detection of promutagens/procarcinogens, we found that AFB1 and 3-MC did not induce a UDS reaction in uninduced FL cells, while in beta-NF induced cells, 10(-6)-10(-4) M AFB1 and 10(-7)-10(-6) M 3-MC elicited a very significant UDS reaction, which was concordant with the results obtained in the UDS assay system using HeLa cells or FL cells supplemented with liver microsomes or using primary cultured hepatocytes as indicator cells. B(a)P elicited the UDS reaction at concentrations of 10(-6)-10(-3) M in beta-NF induced cells, whereas 10(-4)-10(-3) M was required in uninduced cells. The results above indicate that this new design is feasible, but further study is needed to assure its accuracy.

Aflatoxin B1↗
PubMed1984

Hepatic mixed function oxygenase activity and glutathione S-transferase activity in mice following ethanol consumption and withdrawal.

The effect of an 8 day liquid diet containing 7% v/v ethanol and the effect of ethanol withdrawal on several drug metabolizing enzyme activities, cytochrome P-450 content and glutathione S-transferase activity (GST) has been studied in male C57/BL mice. After treatment, hepatic microsomal activities toward benzphetamine (BNZ), biphenyl (BPH) and dimethylnitrosamine (DMN) and cytosolic GST activity towards 1-chloro-2,4-dinitrobenzene (CDNB) were determined. Ethanol treatment caused a differential time dependent increase in the metabolism of the 4 xenobiotics. Increased BPH-4-hydroxylase activity correlated most closely with that of the increased concentration of hepatic P-450. That is, both values were increased (5.8-fold) over controls after 8 days of ethanol treatment. Ethanol withdrawal (24 h) resulted in a 46% reduction in the P-450 content and a 26% reduction in BPH-4-hydroxylase activity compared to the elevated values at day 8. By 48 h, the values were no different from controls. DNA-N-demethylase, BNZ-N-demethylase and GST activities all increased after 4 days of ethanol treatment and remained the same at 8 days. However, ethanol withdrawal resulted in differential time dependent changes in the activities towards BNZ, DMN, and CDNB. While DMN-N-demethylase activity returned to control activity within 24 h, BNZ-N-demethylase activity did not change for the first 24 h of withdrawal, but returned to control activity by 48 h. GST activity had not decreased by 48 h of withdrawal. These data suggest that ethanol induces several cytochrome P-450 isozymes that have a time difference in induction by ethanol and reduction following ethanol withdrawal. Furthermore, ethanol induction of GSTs occurs quickly (4 days) and remains elevated at least 48 h after ethanol withdrawal.

Alcoholism↗
PubMed1978

Effects of phenobarbital and 3-methylcholanthrene pretreatment on size, sedimentation velocity, and mixed function oxygenase activity of rat hepatocytes.

SVA was used to separate liver cells from rats pretreated for 3 days with PB (40 mg/kg intraperitoneally, twice daily) or 3-MC (50 MG/KG AS A SINGLE INJECTIOn). Twelve fractions of cells were collected with s's ranging from 97 mm/hr (fraction1) to 25 mm/hr (fraction 12). Cells in each fraction were sized and counted electronically. PB caused the average volume of the largest cells recovered (fraction 1) to increase to 16, 725 micrometer3 from 10,500 micrometer3 previously reported in untreated animals. The number of cells recovered in the fast-sedimenting fractions (1 to 6) also increased, but there was only a small rise in the average model volume of hepatocytes determined prior to SVA. In cell suspensions analyzed after PB treatment no evidence was found for a discontinuity in the distribution of density-volume characteristics as previously described in hepatocytes from untreated rats. As expected, prior to sedimentation analysis, hepatocyte suspensions from rats treated with PB contained increased cytochrome P-450. The average ratio (n = 4) of P-450 in separated to unseparated cells ranged from 2.75 (fractions 1 + 2) to 0.38 (fractions 11 + 12), giving a 6.8-fold range in quantity of cytochrome per cell. Over this range, cell volume increased 4.2-fold, indicating a gradient in P-450 concentration similar to that previously reported to exist in cells from untreated rat liver. The gradient for AHH activity was 6.7-fold, suggesting that activity of MFO's paralleled the increase in cytochrome concentration. 3-MC pretreatment caused no significant increase in either size or number of cells in the fast-sedimenting fractions, but the discontinuity in density-volume characteristics which distinguished fast and slow sedimenting cells of untreated rats became marked. Furthermore, both the size and number of cells recovered in fractions 7 to 11 (which include the modal peal volume of unseparated hepatocytes) were increased. The gradient of P-450 (OR P1-450) was less steep in 3-MC-treated cells with pooled fractions 1 and 2 containing an average of 4.62 times as much cytochrome as fractions 11 and 12. The gradient for AHH was 4.29 times. The range of cell volume was 3.3-fold over this range. Additional experimental work was performed to determine whether P-450, AHH, or NADPH cytochrome c reductase exhibited differences in activity or concentration per unit of cell volume between cells on either side of fraction 7 where discontinuity had been noted. Each variable was expressed per unit of cell volume in fractions 5 and 9; ratios were compared but were indistinguishable from unity. It was concluded that induction of MFO activity had occurred equally in both populations of cells. Densities were calculated from s and cell volume. Noticeable loss of density followed PB treatment in cells of all sizes. 3-MC had less of an effect on density but enhanced the increment in density observed at fraction 7, which corresponds to the division between cells with distinct sedimentation characteristics...

Animals↗
PubMed2000

Mixed-function oxygenases, oxidative stress, and chromosomal damage measured in lesser scaup wintering on the Indiana Harbor Canal.

During the winter of 1993-1994, male lesser scaup (Aythya affinis) were collected on the heavily polluted Indiana Harbor Canal, East Chicago, Indiana, and examined for several bioindicators of chemical exposure. Livers were analyzed for activities of three cytochrome P450-associated monooxygenases and four measures of oxidative stress. Blood and spleen were analyzed by flow cytometry for chromosomal damage. In a concurrent study, scaup tissues were analyzed for organic and inorganic contaminants. Ethoxyresorufin-O-dealkylase (EROD) activity in livers of scaup collected in January 1994 was significantly higher than in livers of scaup collected in March 1994 or in livers of reference birds. Three hepatic monooxygenase activities were each significantly correlated with polycyclic aromatic hydrocarbon (PAH) concentrations in scaup carcasses. Thiobarbituric acid (TBA) activity in scaup livers was positively correlated with iron, boron, and lead concentrations in livers and polychlorinated biphenyl concentrations in carcasses. TBA activity was negatively correlated with protein-bound thiol activity and mercury concentrations in livers. The coefficient of variation of DNA content in scaup blood cells was correlated with PAH concentrations in scaup carcasses. This is the first field study with birds to demonstrate a correlation between liver monooxygenase activity and carcass PAH concentrations and to show a direct correlation between PAH concentrations in tissues and somatic chromosomal damage in blood.

Animals↗
PubMed1980

Effects of pentachlorophenol on rat liver changes induced by hexachlorobenzene, with special reference to porphyria, and alterations in mixed function oxygenases.

Hexachlorobenzene (HCB, 1000 ppm) and 500 ppm pentachlorophenol (PCP) were fed separately or in combination to female Wistar rats. A control group was provided with standard food without HCB or PCP. Subgroups of 4 rats were killed after 1, 2, 4, 6 and 8 weeks. No significant difference was found between the amounts of HCB accumulated in the livers of the HCB and HCB + PCP fed rats. Administering HCB together with PCP caused a noticeable accumulation of PCP in the liver, compared to the results after administering HCB and PCP separately. In the HCB and HCB + PCP fed groups liver weight increased continuously during the experiments. Microsomal cytochrome P-450, NADPH-cytochrome c reductase, ethoxyresorufin O-de-ethylase, aminopyrine N-demethylase, and glucuronyl transferase increased to a maximum in 2-4 weeks in HCB and HCB + PCP fed rats. Pentachlorophenol accelerates the onset of HCB porphyria, in other words it increases the total urinary porphyrin excretion and causes an earlier disturbance of the porphyrin pattern.

Animals↗
PubMed2006

Induction of mixed-function oxygenase system and antioxidant enzymes in the coral Montastraea faveolata on acute exposure to benzo(a)pyrene.

Components of the cytochrome P(450) monooxygenase system (MFO) and antioxidant enzymes were investigated in the coral Montastraea faveolata exposed to the organic contaminant benzo(a)pyrene (B(a)P). For bioassays the corals were exposed to increasing concentrations of B(a)P (0.01 and 0.1 ppm) for 24 and 72 h, with water renewal every 24 h. Enzymatic activity of catalase (CAT), superoxide dismutase (SOD) and glutathione S-transferase (GST) were measured in host (polyp) and hosted (zooxanthellae) cells. NADPH cytochrome c reductase activity and contents of cytochrome P(450) and P(420) were only measured in the polyp. Antioxidant enzymes CAT and SOD in polyps and zooxanthellae and GST in polyps increased significantly at the highest concentration and maximum time of exposure. Cytochrome P(420) was found in all colonies, and the cytochrome P(450) content was greatest in the colonies from the highest concentrations of contaminant. NADPH cytochrome c reductase activity and the concentration of pigments did not vary between treatments. This is the first report of the induction of both detoxifying mechanisms, the MFO system and antioxidant enzymes on acute exposure to an organic contaminant in the reef-constructing coral species M. faveolata.

Animals↗
PubMed1995

Rainbow trout hepatic mixed-function oxygenase induction by polychlorinated dibenzo-p-dioxins (PCDDs) as a function of time and tissue concentration.

Rainbow trout, dosed orally with 0.060-84 micrograms/kg of [3H]-2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), [14C]-1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (HxCDD), or [14C]-1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) showed dose-dependent increases in hepatic ethoxyresorufin O-deethylase (EROD) activity, up to 250-fold, after 2-16 d. Induction of EROD activity was a sensitive and rapid indicator of exposure to PCDDs. The effects of time after exposure were not dramatic, but generally EROD activity after 2 d was lower than EROD activity after 16 d. Slopes of dose-response curves relating EROD activity to hepatic concentrations of PCDDs significantly decreased and intercepts significantly increased with increasing time of exposure. When fish were grouped by oral doses, only the low doses of TCDD and HpCDD exhibited time-dependent EROD induction, with significantly greater activity 16 d after dosing compared to 2 d. In most cases, hepatic and muscle concentrations of PCDDs did not significantly change over time. Concentrations of PCDDs in liver and muscle accounted for up to 7% of the orally administered dose. Hepatic levels of PCDDs ranged from 20-100 pg/g at the lowest doses to about 1000 pg TCDD/g, 2000 pg HxCDD/g, or 40,000 pg HpCDD/g at the highest doses. Of the PCDD in the liver, approximately one-third to one-half was associated with the postmitochondrial supernatant (PMS). PCDD concentrations in muscle did not span as wide a range of concentrations as did PCDD in liver; fish given low doses had 10 pg/g in muscle whereas fish given high doses had several hundred picograms per gram in muscle for all three PCDDs.

Animals↗
PubMedDate not supplied

No significant effects of sodium aurothiomalate on haem metabolism and mixed function oxygenase activity in patients with rheumatoid arthritis.

OBJECTIVE: Animal studies suggest that gold compounds impair haem synthesis and increase haem degradation and, as a result, reduce activity of the hepatic haemoproteins cytochromes P-450. The aim of this study was to investigate whether intramuscular gold exerts similar effects in patients with rheumatoid arthritis (RA). METHODS: Urinary porphyrin and precursor excretion, erythrocyte protoporphyrin, and antipyrine clearance, were measured in 6 patients with RA before and 10 weeks after commencement of intramuscular gold. RESULTS: Parameters of haem metabolism were unaffected by gold. While antipyrine clearance was not statistically changed after gold treatment, in 3 of the patients there was an average decrease in antipyrine clearance of 23%. CONCLUSION: Further studies examining RA patients at different time points are required to investigate further the possibility of reduced hepatic drug metabolising activity during prolonged treatment with gold.

Adult↗