Administration of testosterone alleviates the constitutive sex difference in rat brain cytochrome P-450

Sex-related difference was observed in the levels of total cytochrome P-450 (P-450) and the mono-oxygenase activity mediated by P-450(b,e), namely, aminopyrine N-demethylase and morphine N-demethylase activity in rat brain microsomes. Male rat brain had higher activity of the above enzymes as compared to the female rat brain. On the other hand, P-450(c,d) mediated 7-ethoxycoumarin O-deethylase and benzo(a)pyrene hydroxylase activity showed no sex-related difference in rat brain. Administration of testosterone elevated the levels of total P-450, aminopyrine N-demethylase and morphine N-demethylase in female rat brain to levels comparable with that of the male rat brain. No significant change was observed in the levels of 7-ethoxycoumarin O-deethylase and benzo(a)pyrene hydroxylase and NADPH cytochrome c reductase. All of the above enzyme levels were unaffected in the male rat brain following the treatment with testosterone. These results indicate that testosterone may regulate the forms of cerebral P-450 that are associated with the sex-related difference observed in rat brain.     

Vanadium: genetical and biochemical investigations

Ammonium metavanadate was studied for its ability to induce mitotic gene conversion and reverse point mutation in the D7 strain of Saccharomyces cerevisiae. Metavanadate increased the convertant and revertant frequencies; the highest activity was observed without metabolic activation. This indicated that the S9 hepatic fraction and yeast cells in logarithmic phase (and containing a high level of cytochrome P450) biotransform vanadate, probably reducing it to vanadyl. In addition, the effect of ammonium metavanadate on the hepatic monooxygenase system was studied in mice by measuring the level of cytochrome P450 and determining the activities of aminopyrine N-demethylase, p-nitroanisole O-demethylase and 7-ethoxycoumarin O-deethylase in mouse liver microsomal fraction. The results indicated that this compound reduced mono-oxygenase activity and also the level of cytochrome P450.     

Hepatic drug metabolism during development in food-restricted female Sprague-Dawley rats.

Hepatic drug metabolism was investigated in female Sprague-Dawley rats fed ad libitum (A) or a restricted diet (R) (implemented from age 1 month), at 1.5, 4.5 and 12 months to determine the short- and long-term effects of caloric restriction. Microsomal cytochrome P-450 content and NADPH cytochrome c reductase activity were not modified by age. While dietary restriction did not affect cytochrome P-450, it significantly increased NADPH cytochrome c reductase activity at all time periods when compared to corresponding A-fed groups. Aniline hydroxylase and aminopyrine N-demethylase activity tended to decrease with age in the A-fed groups but the differences did not prove to be statistically significant. A significant decrease of aminopyrine N-demethylase was observed with age in R rats. A significant reduction of aniline hydroxylase activity was noted in the R groups compared to age-matched A-fed controls. In contrast, aminopyrine N-demethylase activity increased significantly, but only at 1.5 months of age. Glutathione S-transferase activity was augmented between 1.5 and 4.5 months of age, and this was followed by a significant decrease at age 12 months in both A and R groups. Dietary restriction had no effect on this enzymatic activity. The microsomal cholesterol and phospholipid content as well as the cholesterol/phospholipid molar ratio changed significantly between 1.5 and 4.5 months of age but not between 4.5 and 12 months of age. These parameters were unaltered by dietary restriction. In conclusion, in the female Sprague-Dawley rat there are no statistically significant changes in hepatic microsomal components and drug metabolizing capacity between 1.5 and 12 months of age. Dietary restriction resulted in significant changes in enzymes related to drug metabolism which varied with the enzyme examined. In general, these changes were similar after short- or long-term dietary intervention.     

Hepatic microsomal cytochrome P450 system during experimental hookworm infection

Experimental infection of golden hamsters with the hookworm, Ancylostoma ceylanicum, caused a profound decline in the hepatic microsomal cytochrome P450 content. Concomitant decrease was also noticed in aminopyrine N-demethylase and benzo[a]pyrene hydroxylase activities. However, aniline hydroxylase activity was only marginally elevated during the infection. Microsomal markers, viz., cytochrome b5, NADH-cytochrome-c reductase, and glucose-6-phosphatase, were not significantly altered. Hepatic tissue exhibited an accumulation of lipids, especially phospholipids, triglycerides, and cholesterol, resulting in fatty necrosis around the central vein region. Isolated hepatic microsomes showed a decrease in phosphatidylcholine content. Impairment in hepatic mixed function oxidase (MFO) activities was further confirmed by prolongation in hexobarbital sleeping time and zoxazolamine-induced paralysis. The hepatic MFO system of A. ceylanicum-infected hamsters responded qualitatively and quantitatively in a manner similar to that of control hamsters, upon stimulation with selective chemical inducers like phenobarbitone and 3-methylcholanthrene. Kinetic and in vitro substrate binding studies revealed that for aminopyrine the substrate affinity and the maximum enzyme activity (Vmax) were decreased, while for aniline the binding affinity was decreased and the binding capacity was enhanced. Results indicate specific/selective impairment of the hepatic microsomal cytochrome P450 system during hookworm infection and may have many practical implications in toxicology and pharmacology.     

Induction of tolerance in mice and rats to the effect of endotoxin to decrease the hepatic microsomal mixed-function oxidase system. Evidence for a possible macrophage-derived factor in the endotoxin effect

Daily administration of low, non-lethal doses of bacterial endotoxin to mice and rats has been shown to induce tolerance to the effect of an acute challenge dose of endotoxin to decrease the hepatic microsomal drug metabolizing activity, the level of cytochrome P-450, and to increase heme oxygenase activity. The serum collected at various times after injection of endotoxin into control animals when injected into untreated animals markedly depressed aniline hydroxylase activity, ethylmorphine N-demethylase activity, and the level of cytochrome P-450. Tolerant animals were not affected by the post-endotoxin serum injection, suggesting the decreased activity caused by the serum in untreated animals was probably due to endotoxin contained in the serum. Injection of tolerant mice and rats with supernatant medium obtained from cultures of peritoneal macrophages incubated with 100 micrograms/ml of endotoxin caused a loss of hepatic microsomal drug-metabolizing activity, and a decrease in the level of cytochrome P-450. These results suggest that peritoneal macrophages release a factor in response to endotoxin that mediates the decreased hepatic mixed-function oxidase activity.     

Interactions between cyclosporin A, indomethacin and 16,16-dimethyl prostaglandin E2: effects on renal, hepatic and gastrointestinal toxicity in the rat

Rats were treated for 3 or 14 days with cyclosporin A (CsA, 50 mg/kg) or indomethacin (2 or 5 mg/kg) either alone or in combination, or with CsA plus 16,16-dimethylprostaglandin E2 (DMPGE2, 0.25 mg/kg). Hepatic and renal function were unaffected by treatment with indomethacin at either dose and only at the higher dose was severe intestinal ulceration observed. CsA caused renal and hepatic toxicity, evidenced by increased urine N-acetyl-beta-D-glucosaminidase activity, serum urea, creatinine and bilirubin and decreased serum albumin and total protein. In rats cotreated with CsA and either dose of indomethacin the increases in serum urea and creatinine and decreases in serum albumin and total protein were accentuated, but serum bilirubin was not further increased. Intestinal lesions were present in rats treated for 14 days with CsA plus the lower dose of indomethacin, but not in rats treated with either drug alone. In rats treated with DMPGE2 plus CsA, serum urea and creatinine were normal and urine N-acetyl-beta-D-glucosaminidase activity was reduced compared to rats treated with CsA alone, but DMPGE2 cotreatment had no effect on the CsA induced hyperbilirubinaemia. Hepatic microsomal cytochrome P-450 concentration and aminopyrine N-demethylase activity were lower in rats treated with CsA plus indomethacin than in untreated rats or those treated with either drug alone. Coadministration of indomethacin or DMPGE2 had no effect on serum trough CsA levels. The results are interpreted as showing an exacerbation by CsA of the intestinal toxicity of indomethacin, an increase by indomethacin in the renal toxicity of CsA and a protection by DMPGE2 against CsA renal toxicity. Possible mechanisms involving drug interactions and either hepatic cytochrome P-450, renal cyclooxygenase or other renal sites are discussed.     

Effects of rutin and quercetin on monooxygenase activities in experimental influenza virus infection.

The aim of this work is to study the effect of the flavonoids rutin and quercetin on hepatic monooxygenase activities in experimental influenza virus infection (EIVI). EIVI causes oxidative stress in the whole organism. This is confirmed by the rapidly increased concentrations of thiobarbituric reactive substances in influenza-infected mice: lungs - 290%; blood plasma - more than 320%; liver - 230%; brain - 50%. Although known for their antioxidant activities, rutin and quercetin exhibit prooxidant effect in healthy and antioxidant activity in influenza-infected animals. The pretreatment with both flavonoids (20 mg/kg b.w.) restores oxidative damage mostly in the target organ of the infection as well as in the liver of all infected mice (lungs: rutin - 30%, quercetin - 40%, combination - 45%; liver: rutin - 12%; quercetin - 40%; combination - 50%). As far as EIVI causes oxidative stress, toxicosis and inhibition of the hepatic monooxygenase activity, it is important to study the effects of rutin and quercetin on these systems. Both flavonoids induce the level of cytochrome P-450 (rutin - 13%, quercetin - 30%, combination - 22%) but inactivate NADPH-cytochrome c reductase, aminopyrine N-demethylase and analgin N-demethylase on the 5th day of EIVI. Probably, these flavonoids affect different components of the monooxygenase system. These effects could be explained with oxidative hepatic intoxication on the 5th critical day of EIVI as well as higher dose treatment. More data are needed on the antioxidant/prooxidant effects of rutin and quercetin, probably due to specific metabolic and physiological activities, chemical structure, etc.     

Effects of phospholipid-containing hepatoprotectors on cytochrome P-450-dependent antitoxic function of the liver during experimental toxic hepatitis

Phospholipid-containing hepatoprotectors essentiale and eplir inhibited conversion of cytochrome P-450 into cytochrome P-420 and restored aminopyrine N-demethylase and anilinen-hydroxylase activities of cytochrome P-450 in rats during acute hepatitis induced by CCl₄ and allyl alcohol. The polyphenol phytopreparation legalon did not prevent degradation of cytochrome P-450. Differences in the effects of hepatoprotectors on the impaired antitoxic function of the liver are probably associated with the abilities of essentiale and eplir to provide phospholipids for regeneration of endoplasmic reticulum membranes of hepatocytes. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 127, No. 4, pp. 392–394, April, 1999     

Comparative effects of indomethacin on hepatic enzymes and histology and on serum indices of liver and kidney function in the rat

The effects of high-dose indomethacin (three daily dose, 8.5 mg/kg ip) on pathology and histology, on serum and urine biochemistry, and on various hepatic enzyme activities were studied in rats. Hepatic cytochrome P-450 and aminopyrine N-demethylase were decreased by 52-62%, but glucuronyl transferase fell by only 22%. Hepatic glucose-6-phosphatase, aryl esterase, 6-phosphogluconate dehydrogenase and sulphotransferase remained unchanged, while glucose-6-phosphate dehydrogenase increased by 29%. There were no widespread changes in hepatic and renal pathology or histology, but noteworthy was a mild, focal, centrilobular hepatic response. By contrast, there were severe intestinal lesions: the effects on hepatic enzymes might have been partly a consequence of the intestinal damage. There was a reversible uraemia and significant decreases (20-40% below normal) in both serum albumin and protein, while serum levels of creatinine and aspartate-amino-transferase activity remained constant. A reversible N-acetyl-beta-D-glucoseaminidase (NAG) enzymuria occurred (300% above normal), but no significant proteinuria (less than 300 mg/l). Administration of 16, 16-dimethylprostaglandin F2 alpha(0.5 mg/kg iv) concomitantly with the indomethacin greatly ameliorated the intestinal lesions and prevented the decreases in hepatic drug-metabolizing enzymes. Concomitant 16,16-dimethylprostaglandin F2 alpha did not, however, influence the indomethacin-induced decreases in serum protein, albumin or NAG-enzymuria. It was concluded that indomethacin had a highly selective effect causing a decrease in hepatic cytochrome P-450, which was not accompanied by severe damage to hepatocyte structure.     

Comparative effects of indomethacin on hepatic enzymes and histology and on serum indices of liver and kidney function in the rat.

The effects of high-dose indomethacin (three daily dose, 8.5 mg/kg ip) on pathology and histology, on serum and urine biochemistry, and on various hepatic enzyme activities were studied in rats. Hepatic cytochrome P-450 and aminopyrine N-demethylase were decreased by 52-62%, but glucuronyl transferase fell by only 22%. Hepatic glucose-6-phosphatase, aryl esterase, 6-phosphogluconate dehydrogenase and sulphotransferase remained unchanged, while glucose-6-phosphate dehydrogenase increased by 29%. There were no widespread changes in hepatic and renal pathology or histology, but noteworthy was a mild, focal, centrilobular hepatic response. By contrast, there were severe intestinal lesions: the effects on hepatic enzymes might have been partly a consequence of the intestinal damage. There was a reversible uraemia and significant decreases (20-40% below normal) in both serum albumin and protein, while serum levels of creatinine and aspartate-amino-transferase activity remained constant. A reversible N-acetyl-beta-D-glucoseaminidase (NAG) enzymuria occurred (300% above normal), but no significant proteinuria (less than 300 mg/l). Administration of 16, 16-dimethylprostaglandin F2 alpha(0.5 mg/kg iv) concomitantly with the indomethacin greatly ameliorated the intestinal lesions and prevented the decreases in hepatic drug-metabolizing enzymes. Concomitant 16,16-dimethylprostaglandin F2 alpha did not, however, influence the indomethacin-induced decreases in serum protein, albumin or NAG-enzymuria. It was concluded that indomethacin had a highly selective effect causing a decrease in hepatic cytochrome P-450, which was not accompanied by severe damage to hepatocyte structure.     

Indomethacin induced hepatic alterations in mono-oxygenase system and faecal clostridium perfringens enterotoxin in the rat

The administration of indomethacin to rats, at the dose of 10 mg/kg once daily for three days, caused a loss of microsomal cytochrome P-450 and cytochrome b5 in the liver, and a fall in drug-metabolizing enzyme activities (i.e. aminopyrine N-demethylase, NADP cyt. c. reductase). Indomethacin also induced intestinal lesions and a significant increase in Clostridium perfringens enterotoxin levels in the feces at 24 hours after both the second and third day of treatment.The above findings suggest that the development of intestinal lesion and the accompanying release of Clostridium perfringens enterotoxin, as well as hepatic enzyme alterations in the rat, result from indomethacin administration.Some of the data in this paper were presented at the Meeting of British Pharmacological Society in Ireland, July 6th–8th, 1988.     

Impairment of hepatic cytochrome P-450-dependent monooxygenases by the malaria parasite Plasmodium berghei

The effect of Plasmodium berghei infection on hepatic monooxygenase activities and cytochrome P-450 contents was investigated in mice. NIH/NMRI or A/J mice infected with active P. berghei showed 30-40% decreases in hepatic cytochrome P-450 contents and the ability to metabolize the test substrates, ethylmorphine and benzo(a)pyrene. These decreases were observed during the erythrocytic stage of the infection, but not during the initial exoerythrocytic stage, or after heat-inactivated sporozoites were injected. These results strongly suggest that malaria infections may significantly impair the capacity of the liver to metabolize drugs, carcinogens, and other foreign compounds.     

Effect of endotoxin to differentially affect cytochrome P-450 monooxygenase activities of untreated rats and animals induced with phenobarbital or 3-methylcholanthrene

The effect of endotoxin in decreasing the cytochrome P-450-dependent metabolism of aniline, aminopyrine and ethoxycoumarin was examined in untreated rats, and in rats pretreated with either phenobarbital or 3-methylcholanthrene. Ethoxycoumarin metabolism was determined at two substrate concentrations (5 microM and 500 microM) to determine the effect of endotoxin on the high and low affinity enzyme activities. In untreated animals, endotoxin depressed both aniline and ethoxycoumarin metabolism by the high and low affinity enzymes by approximately 70%, but aminopyrine was decreased by only 47%. In phenobarbital pretreated rats, endotoxin decreased enzyme activities less than in untreated animals. Aniline metabolism and low affinity ethoxycoumarin metabolism were decreased by only 24%, and aminopyrine metabolism was decreased by 35%. The high affinity ethoxycoumarin metabolism was least affected, being decreased by only 12%. In 3-methycholanthrene pretreated rats, aniline and ethoxycoumarin (500 microM) metabolism were decreased by approximately 45%, but aminopyrine metabolism was only decreased by 20%. In these animals, endotoxin did not significantly affect the activity of ethoxycoumarin metabolism assayed with the low substrate concentration. Endotoxin decreased total cytochrome P-450 level of untreated rats by 32%, of phenobarbital pretreated rats by 39%, and in 3-methylcholanthrene pretreated animals the decrease was only 21%. Heme oxygenase activity of untreated animals was induced most by endotoxin administration and least in phenobarbital treated rats. The data suggest that endotoxin may differentially affect the various isozymes of cytochrome P-450 associated with the metabolism of aniline, aminopyrine and ethoxycoumarin. The results also suggest that the isozymes associated with these activities in untreated, phenobarbital or 3-methylcholanthrene pretreated rats may differ in their sensitivity to the effect of endotoxin.     

Factors involved in the down-regulation of cytochrome P450 during Listeria monocytogenes infection

The activation of host defense mechanisms has been shown to cause a depression in hepatic cytochrome P450-mediated metabolism in rodents and humans. In a previous study, it was demonstrated that the Gram-positive bacteria Listeria monocytogenes causes a down-regulation of hepatic cytochrome P450 and related substrate metabolism as a result of a pretranslational depression of apoprotein synthesis. The objectives of this study were to determine whether the effect of listeria on hepatocyte cytochrome P450 involves hepatic nonparenchymal cells and whether the hemolysin, secreted only by hemolytic forms of the bacteria, plays any part in mediating this effect. Total cytochrome P450 levels as well as ethoxyresorufin-O-dealkylase (EROD) and benzyloxyresorufin-O-dealkylase (BROD) activities were significantly reduced in hepatic microsomes isolated from mice infected in vivo for 48 h with 15U listeria, whereas the same dose of the avirulent non-hemolytic M3D strain had no effect. Listeria (15U) significantly depressed hepatocyte EROD and BROD activities after 24 h incubations with liver cell cultures containing hepatocytes and nonparenchymal cells, as the result of both a direct effect on the hepatocyte and an interaction of listeria with hepatic nonparenchymal cells. The M3D strain of listeria had no effect on cytochrome P-450-mediated metabolism in isolated cells, confirming that hemolysin is an essential component of the mechanism responsible for the down-regulation of cytochrome P450 during listeria infections.     

In vivo and in vitro inhibition of hepatic microsomal drug metabolism by ketoconazole

Ketoconazole (KC), a broad spectrum antifungal drug, has been recognized recently as a cause of hepatic injury. The mechanism of the adverse reaction remains unclear: a metabolic idiosincrasy has been suggested. However as a substituted imidazole, KC might be expected to interfere with the hepatic microsomal mixed function oxidases. Ethylmorphine N-demethylase (E-DM) and aniline hydroxylase (A-OH) activities were determined in rat liver microsomes in the presence of increasing amounts of KC. Both were inhibited in an exponential fashion. The E-DM inhibition was almost complete at concentrations greater than 250 microM and was of the mixed type. A much weaker effect was observed for A-OH. A significant inhibition of E-DM was also observed when KC was administered in vivo to rats either orally for 7 days at the dose of 100 mg/kg/day (P less than 0.02) or intraperitoneally for 4 days at the dose of 50 or 100 mg/kg day (P less than 0.01 or P less than 0.001 respectively). A-OH activity was significantly reduced (P less than 0.01) only after ip administration of 100 mg/kg/day of the drug for 4 days. Neither the amount of cytochrome P-450 nor NADPH cytochrome c reductase activity were affected at the doses considered. These data show that KC interferes with hepatic oxidative drug metabolism and suggest that this mechanism might be involved in the unwanted side effects of therapy with KC.     

In vivo and in vitro inhibition of hepatic microsomal drug metabolism by ketoconazole.

Ketoconazole (KC), a broad spectrum antifungal drug, has been recognized recently as a cause of hepatic injury. The mechanism of the adverse reaction remains unclear: a metabolic idiosincrasy has been suggested. However as a substituted imidazole, KC might be expected to interfere with the hepatic microsomal mixed function oxidases. Ethylmorphine N-demethylase (E-DM) and aniline hydroxylase (A-OH) activities were determined in rat liver microsomes in the presence of increasing amounts of KC. Both were inhibited in an exponential fashion. The E-DM inhibition was almost complete at concentrations greater than 250 microM and was of the mixed type. A much weaker effect was observed for A-OH. A significant inhibition of E-DM was also observed when KC was administered in vivo to rats either orally for 7 days at the dose of 100 mg/kg/day (P less than 0.02) or intraperitoneally for 4 days at the dose of 50 or 100 mg/kg day (P less than 0.01 or P less than 0.001 respectively). A-OH activity was significantly reduced (P less than 0.01) only after ip administration of 100 mg/kg/day of the drug for 4 days. Neither the amount of cytochrome P-450 nor NADPH cytochrome c reductase activity were affected at the doses considered. These data show that KC interferes with hepatic oxidative drug metabolism and suggest that this mechanism might be involved in the unwanted side effects of therapy with KC.     

Carbon tetrachloride hepatotoxicity in endotoxin tolerant and polymyxin B-treated rats

Gut-derived endotoxin has been implicated in the hepatotoxic effects of CCl4. The present study has investigated whether two procedures known to block LPS effects would alter the action of CCl4 to decrease hepatic cytochrome P-450 and microsomal drug-metabolizing activity. Administration of polymyxin B or induction of LPS tolerance were shown to attenuate the effect of CCl4 administration to increase SGOT and SGPT levels, signs of hepatic damage. Polymyxin B administration but not LPS tolerance caused a slight decrease in cytochrome P-450. In pretreated animals given CCl4, only those which had received polymyxin B showed a reduced effect of CCl4 to alter cytochrome P-450 level and activity. However, the apparent protective effect was of the same magnitude as the loss of cytochrome P-450 caused by polymyxin B itself. These results suggest that the ability of polymyxin B to ablate the CCl4 loss of P-450 might be due to a reduced metabolic activation of CCl4 by P-450 and not due to any anti-LPS activity. The results suggest that gut-derived LPS does not participate in the effect of CCl4 decreasing cytochrome P-450-mediated reactions. However, participation of LPS in other hepatotoxic effects of CCl4 is not excluded.     

Effect of Plasmodium yoelii nigeriensis infection and chloroquine on the hepatic mixed function oxidase system of mice

Plasmodium yoelii nigeriensis infection in albino mice significantly altered the hepatic microsomal mixed function oxidase system. Cytochrome P-450 (the terminal monooxygenase) and other monooxygenases, viz. aniline hydroxylase, aminopyrine-N-demethylase and benzo(a)pyrene hydroxylase were significantly lowered while microsomal heme showed 4-fold increase at 80% parasitaemia. Noticeable impairment in the other components like NADH:cytochrome b5 reductase, NADPH:cytochrome c reductase, cytochrome b5 and glucose-6-phosphatase was also observed. Oral treatment of normal and P. y. nigeriensis infected mice with chloroquine (64 mg per kg body weight for 4 days) caused lowering of mixed function oxidase activities which however showed a recovering trend, a week after cessation of treatment.     

Effects of ethanol on microsomal drug metabolism in aging female rats. I. Induction

The purpose of this study was to determine how aging affects the induction by ethanol or acetone of the hepatic microsomal monooxygenase system of female Fischer 344 rats. Young-adult, middle-aged and old rats (4, 14 and 25 months) were fed an ethanol-containing or control liquid diet for 15 days. Cytochrome P-450, cytochrome c reductase, aniline hydroxylase, nitrophenol hydroxylase, nitroanisole O-demethylase and benzphetamine N-demethylase activities were measured in hepatic microsomes. All of the drug metabolism activities except benzphetamine N-demethylase were 20-35% lower in old than in young-adult rats fed the control diet. In addition, the increase in drug metabolism produced by feeding the regular ethanol diet (36% of calories as ethanol) was 50-60% lower in the old rats. However, there was no difference in the magnitude of ethanol induction when ethanol intakes were matched. The effects of chronic acetone consumption (1.2g/day per kg body weight for 15 days) paralleled those of ethanol consumption, except that the extent of induction was greater with acetone. Acetone-induced levels of hepatic microsomal cytochrome P-450, nitrophenol hydroxylase, nitroanisole O-demethylase and aniline hydroxylase were similar in all three age groups. The results of this study indicate that induction of hepatic microsomal drug metabolism by ethanol or acetone is unaffected by the aging process.     

Changes in hepatic xenobiotic-metabolising enzymes in mouse liver following infection with Leishmania donovani

Infection of mice with Leishmania donovani resulted in decreased activities of several liver enzymes involved in the metabolism of xenobiotics. Microsomal membranes from infected livers contained reduced amounts of cytochromes P450 and b5 and NADPH-cytochrome P450 reductase. Several cytochrome P450 isoenzymes (P450-PB1, P450-PB3, P450-PCN and P450-UT1) and P450-mediated reactions (aminopyrine demethylase, aniline hydroxylase, benzphentamine demethylase and ethoxycoumarin deethylase) were affected similarly. The metabolism of two carcinogens (nitrosodimethylamine and 7,12-dimethylbenz[a]anthracene) by liver microsomal membrane preparations was also reduced. Leishmania infection caused an increase of cytosolic epoxide hydrolase and microsomal epoxide hydrolase and NADH-cytochrome b5 reductase were unaffected. The results suggest that Leishmania-infected animals are likely to have altered responses to exogenous toxins compared to uninfected animals.