Drug metabolism in extrahepatic diseases.
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Animals↗
Biomedical subjects
G C Farrell
Publications and source records attributed to G C Farrell.
Hepatitis B in Australia: determinants of intrafamily spread.
Strategies for the control of hepatitis B virus (HBV) infection rely on information about the modes of spread and the numbers of 'at risk' individuals in particular community subgroups. This study prospectively examined 377 family and household contacts of 145 patients with HBV infection to determine the incidence of and factors determining intrafamily spread. Two hundred and forty were contacts of 68 Asian patients and 137 were contacts of 77 Caucasian patients. Serological examination of all contacts demonstrated that 161 (43%) had HBV markers including 60 (16%) who were HBsAg positive. HBV transmission within families was greater if the index case was Asian rather than Caucasian (p less than 0.001), had an HBsAg positive mother rather than an HBsAg positive father (p less than 0.01), was HBeAg positive rather than HBeAg negative (p less than 0.002), and had chronic rather than acute HBV infection (p less than 0.001). However birthplace, family size, and the activity of the liver disease of the index case did not influence HBV transmission. Within Asian families, the risk of non-sexual and non-vertical transmission of hepatitis B appeared to be as high as 18% and continued after the first three years of life. It is concluded that hepatitis B prevention programmes should include vaccination of families of chronic HBV carriers, particularly those from endemic regions such as Asia.
Adolescent↗
Altered regulation of cytochrome P-450 enzymes in choline-deficient cirrhotic male rat liver: impaired regulation and activity of the male-specific androst-4-ene-3,17-dione 16 alpha-hydroxylase, cytochrome P-450UT-A, in hepatic cirrhosis.
Total microsomal cytochrome P-450 levels were decreased, to about 50% of control, in liver of male rats made cirrhotic by the prolonged intake of a choline-deficient diet. We have suggested previously that this decrease in cytochrome P-450 levels is not a generalized one, but is selective for certain forms of the enzyme. In the present study, levels of six cytochrome P-450 forms including the sex-specific cytochrome P-450 forms, P-450UT-A, P-450PCN-E, and P-450UT-l, were quantitated immunochemically in hepatic microsomes prepared from control and cirrhotic male rats and were related to changes in the regioselectivity of cytochrome P-450-mediated androst-4-ene-3,17-dione hydroxylation in these fractions. The principal finding of this study was that the male-specific androst-4-ene-3,17-dione 16 alpha-hydroxylase was decreased in cirrhotic microsomes to about 20% of control. The content of P-450UT-A decreased concurrently from about 0.40 to less than 0.01 nmol/mg of microsomal protein. Other pathways of androst-4-ene-3,17-dione hydroxylation were also affected, but to different extents than the 16 alpha-hydroxylase. 6 beta-Hydroxylation decreased in cirrhotic microsomes to about 45% of control, despite a marked decrease in P-450PCN-E from 0.27 to less than 0.002 nmol/mg of microsomal protein. The rate of androst-4-ene-3,17-dione 7 alpha-hydroxylation underwent a less pronounced reduction in cirrhosis to about two-thirds of control microsomal activity, and levels of the cytochrome P-450 associated with this activity, P-450UT-F, were decreased in proportion with the decrease in total microsomal cytochrome P-450. 16 beta-Hydroxylase activity was unaffected by the cirrhotogenic process. From spectral binding studies it was apparent that androst-4-ene-3,17-dione elicited a high affinity type I interaction in control microsomal fractions (Ks = 4.5 microM), whereas no interaction was apparent in cirrhotic liver microsomes. Levels of three other forms of cytochrome P-450--P-450PB-C (a constitutive form inducible by phenobarbital), P-450ISF-G (a major isosafrole-inducible form), and P-450UT-I (the major female sexually-differentiated isozyme)--were apparently unaltered in cirrhosis. These findings are consistent with the assertion that specific forms of cytochrome P-450 are subject to altered regulation in hepatic cirrhosis.
Androstenedione↗
Effects of primaquine on hepatic microsomal haemoproteins and drug oxidation.
Administration of the antimalarial agent primaquine to male rats (50 mg/kg i.p. daily for 4 days) resulted in a 30% decrease in hepatic microsomal cytochrome P-450 (P-450) content; levels of other microsomal haemoproteins were unaltered. Kinetic analysis of 2 mixed-function oxidase activities (aminopyrine N-demethylase and aniline p-hydroxylase) in primaquine-pretreated rat liver microsomes revealed a significant and similar decrease in the maximal reaction velocities of these enzymes (Vmax), but the apparent Michaelis constants (Km) were not changed. The activity of mitochondrial delta-aminolaevulinic acid synthetase (the rate-limiting step in haem biosynthesis) was normal in primaquine-pretreated rat liver but haem oxygenase activity (the rate-limiting step in haem degradation) was elevated approximately 2-fold. Haem availability for haemoprotein assembly (determined as the haem-saturation ratio of the cytosolic haemoprotein tryptophan pyrrolase) was also normal although the absolute activity of tryptophan pyrrolase was decreased after primaquine pretreatment. In order to facilitate an analysis of the P-450 isozyme profile in control and primaquine-treated rat liver, total microsomal P-450 was isolated by hydrophobic affinity chromatography on n-octylamino-Sepharose 4B. Densitometry of stained polyacrylamide gels following electrophoresis of these partially-purified P-450 fractions indicated that primaquine exposure did not selectively decrease any of the 3 protein bands in the P-450 molecular weight region (48-56 kD). These observations, when considered together, suggest that primaquine may affect P-450 and mixed-function oxidase activity by inhibition of protein synthesis. The characteristic rapid turnover rates of P-450 isozymes may predispose these haemoproteins to the toxic effects of primaquine whereas those haemoproteins that turn over less rapidly, such as cytochrome b5, appear to be less susceptible. Microsomal haem oxygenase activity may be elevated after primaquine administration since lowered haemoprotein requirements for haem could result in excess haem levels within the hepatocyte.
Animals↗
Incorporation of haemoglobin haem into the rat hepatic haemoproteins tryptophan pyrrolase and cytochrome P-450.
After its administration to intact rats, haemoglobin haem was incorporated into hepatic tryptophan pyrrolase as shown by the marked increase in functional constitution of this enzyme. Incorporation of haemoglobin haem into cytochrome P-450 was demonstrated in intact rats and in the isolated rat liver perfused with haemoglobin-free medium. In both systems, haemoglobin haem restored cytochrome P-450 content and its dependent mixed-function-oxidase activity after substrate-induced destruction of the cytochrome P-450 haem moiety. Further confirmation that haemoglobin haem could be incorporated prosthetically into cytochrome P-450 was achieved by administration of [3H]haemoglobin to rats and subsequent isolation and characterization of radiolabelled substrate-alkylated products of cytochrome P-450 haem. Our findings indicate that, although hepatic uptake of parenteral haemoglobin is slower than that of haem, it appears to serve as an effective haem donor to the intrahepatic 'free' haem pool. Thus parenteral haemoglobin may warrant consideration as a therapeutic alternative to haem in the acute hepatic porphyrias.
Allylisopropylacetamide↗
Mechanistic aspects of the inhibition of microsomal drug oxidation by primaquine.
The kinetics of inhibition of microsomal drug oxidation (as aminopyrine N-demethylase activity) by the antimalarial agent primaquine were found to be concentration-dependent. Lower concentrations of primaquine (0-40 microM) elicited slope-hyperbolic, intercept-hyperbolic noncompetitive (mixed) inhibition with an inhibitor equilibrium-dissociation constant (Ki) of 21 microM. On the other hand, primaquine concentrations greater than 40 microM elicited essentially simple competitive inhibition as judged from Lineweaver-Burk and Dixon analysis with appropriate replots (Ki = 23 microM). The coincident Ki values suggest that the same enzyme-inhibitor complex is involved in inhibition over all concentrations of primaquine tested. The apparent change in kinetics was accounted for in terms of a four-step interaction scheme involving a ternary enzyme-substrate-inhibitor complex that catalyses substrate oxidation at a slower rate than the binary enzyme-substrate complex. Competitive inhibition reflects the likelihood that the ternary complex does not form at all, presumably due to reduced accessibility of the active site to substrate. A good correlation was found between the Ki values for the inhibition of aminopyrine N-demethylase activity (21 or 23 microM) and the modulation of aminopyrine binding (26 microM) by primaquine. These findings suggest that the inhibition of aminopyrine N-demethylase activity by primaquine is mediated via an interaction with the oxidised form of cytochrome P-450. In addition, the apparent change in inhibition kinetics suggests a concentration-dependent change in the capacity of primaquine to modulate substrate binding to cytochrome P-450 as well as the formation of a P-450-aminopyrine-primaquine ternary complex.
Aminopyrine N-Demethylase↗
New heterocyclic modifiers of oxidative drug metabolism--I. 6-Substituted-2-aminobenzothiazoles.
A series of 6-substituted-2-aminobenzothiazoles(2-AB) was synthesized and evaluated as in vitro inhibitors of microsomal mixed-function oxidase activity (as aminopyrine N-demethylase) from phenobarbitone-induced rat liver. Using physiochemical parameters and multiple regression analysis a quantitative structure-activity relationship (QSAR) was derived in which 82% of the data variance was accounted for in terms of the hydrophobic character of the inhibitor and the molar refractivity of the 2-AB 6-substituent. In contrast, literature equations derived from earlier studies with heterocyclic systems possessing non-polar substitutents underestimated by up to an order of magnitude the potency of the present compounds. Kinetic studies revealed that 6-n-propoxy-2-AB, one of the more potent compounds, was a pure competitive inhibitor of aminopyrine N-demethylase activity (Ki = 60 microM from Dixon analysis), suggesting that the binding of substrate and inhibitor is mutually exclusive at the cytochrome P-450 active site. Binding studies indicated that most 2-AB derivatives elicited mixed type I/reverse type I optical difference spectra in phenobarbitone-induced microsomes. The overlap of these components resulted in non-linear double reciprocal plots of the spectral titrations and precluded the determination of binding parameters. In contrast, the more potent inhibitors (the 6-propoxy and 6-butoxy derivatives of 2-AB) were type I ligands with quite high affinity for ferric cytochrome P-450. Although no quantitative relationship was apparent between inhibition and spectral binding affinity a good correlation (r = 0.93) was observed between inhibition potency (I50) and the capacity of ten 2-AB derivatives to prevent substrate(aminopyrine) binding to cytochrome P-450. These findings suggest that 2-AB derivatives may inhibit microsomal oxidation via a direct competitive effect on substrate binding to cytochrome P-450. The present study also demonstrates that substitution of heterocyclic systems with hydrophilic groups does not necessarily produce weak inhibitors of mixed-function oxidase activity, and that extrapolation of existing QSAR equations to new inhibitor series must be interpreted with caution.
Aminopyrine N-Demethylase↗
Drug metabolism in cirrhosis. Selective changes in cytochrome P-450 isozymes in the choline-deficient rat model.
The effect of a choline-deficient diet on microsomal cytochrome P-450 and mixed-function oxidase (MFO) activity was investigated in relation to the development of nutritional cirrhosis. In rats that received the choline-deficient diet for 28 weeks cirrhosis was evident macroscopically and histologically; control rats that received an identical diet supplemented with choline had normal livers. Microsomal cytochrome P-450 and cytochrome b5 were reduced in cirrhotic liver to 50% of control levels. Three MFO activities (ethylmorphine N-demethylase, aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase) were also reduced to 40-70% of control levels. However, the turnover number for the O-deethylation of 7-ethoxycoumarin was not reduced in cirrhotic liver. This finding suggested that certain drug oxidations may be selectively depressed in nutritional cirrhosis. To examine the possibility that selective changes in MFO activity may reflect the suppression of certain cytochrome P-450 isozymes, partially purified fractions of the cytochrome were prepared after solubilisation and hydrophobic affinity chromatography (on n-octylamino-Sepharose 4B) of cirrhotic and control liver microsomes. Analysis of these fractions by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and laser densitometry indicated that a protein band of apparent minimum molecular weight 50.5 kD was primarily affected in cirrhotic rat liver microsomes. Levels of two other bands (apparent minimum molecular weight 48 and 52.5 kD) appeared essentially unaltered. Additional electrophoretic studies, conducted under non-reduced conditions, indicated the haemoprotein nature of protein bands in the 48-55 kD region. These data strongly suggest that cirrhosis produced in rats by a choline-deficient diet is associated with selective decreases in oxidative drug metabolism and individual cytochrome P-450 isozymes.
Animals↗
Selective reactivation of steroid hydroxylases following dissociation of the isosafrole metabolite complex with rat hepatic cytochrome P-450.
In order to elucidate the isozyme specificity of complex formation between cytochrome P-450 and the isosafrole metabolite the effect of complex dissociation on different steroid hydroxylation pathways was studied in hepatic microsomal fractions. Isosafrole induction was found to increase the 16 beta- and 7 alpha-hydroxylation of androst-4-ene-3,17-dione approximately 2.8- and 1.7-fold, respectively, whereas the 16 alpha-hydroxylation pathway was decreased to about one-quarter of control activity; 6 beta-hydroxylation was unchanged from control activity. More striking changes were apparent following dissociation of the isosafrole metabolite from its complex with ferricytochrome P-450 by the steroid substrate. Thus an approximate fourfold elevation of 16 beta-hydroxylase activity was observed after displacement and 6 beta-hydroxylation increased about twofold; 7 alpha-hydroxylase activity was decreased to 0.75-fold of undisplaced activity and 16 alpha-hydroxylase activity was unchanged. These data provide convincing evidence that at least two forms of phenobarbital-inducible cytochrome P-450 (cytochromes P-450PB-B and P-450PB/PCN-E) are present to some extent in a catalytically inactive complexed state in isosafrole-induced rat hepatic microsomes. Furthermore, there is now evidence to suggest that the constitutive isozymes cytochrome P-450UT-A and cytochrome P-450UT-F are not complexed to any degree in hepatic microsomes from isosafrole-induced rats.
Androstenedione↗
Effects of portal vein ligation on sex hormone metabolism in male rats: relationship to lowered hepatic cytochrome P450 levels.
Hepatic cytochrome P450 levels in male rats fall after portal vein ligation, a procedure that produces total hepatic bypass of portal blood. The present study was undertaken to examine whether changes in sex hormone metabolism could account for these lowered cytochrome P450 levels. Portal vein ligation resulted in testicular atrophy and low serum testosterone concentrations. Serum luteinizing hormone levels were also reduced, suggesting that testicular atrophy was secondary to suppression of the hypothalamic-pituitary-gonadal axis. Serum estrone and estradiol concentrations were significantly increased after portal vein ligation, while the magnitude and delayed onset of increases in urinary total estrogen excretion suggested that this was due largely to increased estrogen production. In male rats, both castration (at 12 wk) and exogenous estrogen administration resulted in changes in hepatic cytochrome P450 levels and ethylmorphine N-demethylase activity that were qualitatively similar to those seen after portal vein ligation. In female and castrated male rats, however, cytochrome P450 was not affected by portal vein ligation. Testosterone supplementation corrected the changes of cytochrome P450 levels in castrated male rats but did not have this effect in portal vein-ligated male rats. It is concluded that changes in sex hormone metabolism do occur after portal vein ligation and may contribute to alterations in cytochrome P450 and drug-metabolizing enzyme activity. Decreased levels of serum testosterone, however, do not alone account for the changes in hepatic drug metabolism in this model, and suppression of a hypothalamic-pituitary factor appears to be important.
Animals↗
Increased binding of benzo[a]pyrene metabolites to lymphocytes from patients with lung cancer.
This study was performed to determine whether lymphocytes from individuals with lung cancer were more likely to bind benzo[a]pyrene (BP) metabolites in an in vitro test. The in vitro system consisted of peripheral blood lymphocytes incubated with increasing concentrations of [3H] benzo[a]pyrene in the presence of beta-naphthoflavone-induced rat liver microsomes and a NADPH-generating system. The radioactivity bound to a TCA-precipitate of the lymphocytes was determined. The apparent affinity (Km) and maximal binding (Vmax) of this binding were calculated from double reciprocal plots of the data. Seven patients with primary lung cancer (squamous cell carcinoma and undifferentiated small cell carcinoma), none of whom had smoked for at least 2 months, were studied as were 10 lung cancer free smokers, and the results compared with 13 age- and sex-matched controls. In lymphocytes from patients with primary lung cancer, Vmax of radiolabel bound to TCA-precipitable material was almost double that of non-smoking controls (205 +/- 19.2 pmol X 2h X 10(6) cells vs. 121 +/- 10.8 pmol X 2h X 10(6) cells, mean +/- S.E.M., P less than 0.01). Among individuals without lung cancer, smokers did not differ from non-smokers. In addition, there was no difference in Km of radiolabel binding to lymphocytes from patients in all 3 groups. It is concluded that binding of carcinogenic metabolites to cell components is increased in patients with lung cancer. Further studies are required to determine whether this increased binding is related to individual susceptibility of some smokers to lung cancer.
Adult↗
Cerebrospinal fluid gamma-aminobutyric acid levels in dogs with chronic portosystemic encephalopathy.
Cerebrospinal fluid (CSF) gamma-aminobutyric acid (GABA) levels were measured in a dog model of spontaneous chronic portosystemic encephalopathy. Dogs with congenital portacaval shunts (intra- or extra-hepatic) develop neurological features of abnormal psychomotor behaviour and depressed consciousness that are consistent with the symptoms of chronic portosystemic encephalopathy in humans. In the five dogs studied, plasma ammonia was elevated, as was CSF tryptophan, both usual biochemical abnormalities in portosystemic encephalopathy. CSF levels of GABA in five dogs with portosystemic encephalopathy (100 +/- 13 pmol/ml) were not significantly different from those in five control dogs (96 +/- 14 pmol/ml). CSF levels of GABA were not altered after ammonia infusion. If enhanced GABA-ergic neurotransmission, due to influx of gut-derived GABA into the brain, is responsible for the pathophysiology of chronic portosystemic encephalopathy in this model, it is not reflected by increased levels of GABA in CSF.
Ammonia↗
Inhibition of antipyrine metabolism by interferon.
Antipyrine clearance was measured before and 1 day after administration of a single intramuscular dose of recombinant human leukocyte alpha A interferon. In the nine patients studied, antipyrine clearance was reduced after interferon from 0.49 (0.21-1.13) ml kg-1 min-1 (median (range)) to 0.41 (0.20-1.07) ml kg-1 min-1, P less than 0.01. In individual patients, the decrement in antipyrine clearance was variable, ranging from 5-47% (median, 16%). This study provides the first direct evidence that interferon inhibits hepatic oxidative drug metabolism in humans and alerts clinicians to the possibility of potentially toxic drug-drug interactions.
Adult↗
Hepatic heme metabolism and cytochrome P450 in cirrhotic rat liver.
Cytochrome P450 levels are often low in the cirrhotic liver but the reason for this has not been established. Because changes in heme metabolism may reduce hepatic levels of cytochrome P450, the relationship of heme turnover to cytochrome P450 levels has been examined in rats with cirrhosis. Cirrhosis was produced by repeated carbon tetrachloride inhalation. In animals with cirrhosis, hepatic microsomal cytochrome P450 content was significantly less (32%) than in controls. Heme synthesis was assessed by measuring the activity of mitochondrial delta-amino-levulinic acid synthetase and also by determining the incorporation (within 30 min) of radiolabeled delta-aminolevulinic acid into the microsomal heme fraction. Both these parameters were normal in rats with CCl4-induced cirrhosis. In addition, the activity of microsomal heme oxygenase, the rate-limiting enzyme in catabolism of heme to bilirubin, was not altered. Cytochrome P450 heme degradation was then determined directly by injecting radiolabeled delta-aminolevulinic acid and measuring radioactivity in CO-binding particles (microsomes incubated with protease to remove cytochrome b5) prepared at various times thereafter. By this method, the degradation rate of cytochrome P450 heme did not differ between rats with cirrhosis and controls. Finally, the availability of hepatic heme for formation of hemoproteins was deemed to be satisfactory in cirrhotic liver because tryptophan pyrrolase saturation was comparable with controls, and also because heme administered in vivo did not enhance hepatic clearance of the cytochrome P450 substrate antipyrine. The failure to find defective heme biosynthesis or accelerated heme breakdown and the evidence that heme is available in amounts that do not restrict hemoprotein formation indicate that aberrant heme metabolism is not the cause of low cytochrome P450 levels in this rat model of cirrhosis.
Aminolevulinic Acid↗
Different effects of carbon tetrachloride toxicity and cirrhosis on substrate binding to rat hepatic microsomal cytochrome P-450.
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Animals↗
Microsomal protein synthesis and induction of cytochrome P-450 in cirrhotic rat liver.
In order to determine whether non-specific defects of protein synthesis account for reduced levels of cytochrome P-450 in cirrhotic liver, total microsomal protein synthesis and response to microsomal enzyme-inducing agents have been examined in rats. Cirrhosis was produced by administration of carbon tetrachloride (CCl4) and phenobarbitone for 10 weeks. Ten days after stopping these agents, cytochrome P-450 levels were 30% lower in cirrhotic liver than in controls (p less than 0.0001). However, total microsomal protein synthesis, determined in vivo by administration of [3H]-leucine, was similar in cirrhotic (1347 +/- 420 dpm/mg protein) and control (1317 +/- 303 dpm/mg protein) liver. Three separate types of microsomal enzyme-inducing agents, phenobarbitone, beta-naphthoflavone, and pregnenolone 16 alpha-carbonitrile, were administered to cirrhotic and normal rats. In both groups of animals increases of total cytochrome P-450 and selective changes of cytochrome P-450 isoenzymes (assessed by mixed function oxidase activity towards four substrates) were qualitatively and quantitatively similar. It is concluded that hepatocytes of cirrhotic rat liver synthesize microsomal protein at a normal rate but less of it is cytochrome P-450, and the entire process of enzyme induction is intact. Thus, it appears likely that altered regulation of basal levels of cytochrome P-450 rather than an altered response of the liver is responsible for the lowered cytochrome P-450 content of cirrhotic rat liver.
Aminopyrine↗
Accuracy and clinical utility of simplified tests of antipyrine metabolism.
High-performance liquid chromatography (h.p.l.c.) was used to measure plasma antipyrine concentrations in sixteen healthy subjects; five males, six females taking oral contraceptive steroids (OCS) and five age-matched females not taking OCS. Following oral administration of the drug, antipyrine clearance could be determined with similar precision and accuracy from plasma concentrations at two selected times (4 h and 24 h) ('two-sample antipyrine clearance test') as from six samples taken over two to three elimination half-lives (t1/2) of the drug ('conventional antipyrine clearance test'). Provided times for plasma sampling were modified appropriately, the two-sample antipyrine clearance test also gave reliable results in four patients taking phenytoin (sampling times 4 h and 8 h) who had significantly enhanced antipyrine clearance, and in nine patients with severe liver disease (using 4 h and 48 h) in whom antipyrine clearance was impaired. Urinary excretion of antipyrine metabolites (from 0-24 h) was determined in the above groups. Antipyrine systemic clearance correlated best with the percentage of administered dose excreted as 4-hydroxyantipyrine (r = 0.66, P less than 0.001) but also with 3-hydroxymethylantipyrine (r = 0.54, P less than 0.001) and with total metabolites excreted (r = 0.60, P less than 0.001). Total antipyrine metabolites excreted in urine in 24 h were significantly different from controls only in patients with liver disease (14 +/- 7.6% of administered dose vs 62 +/- 14%, P less than 0.001). The relative proportion of antipyrine metabolites did not appear to be altered when hepatic mixed function oxidation was induced by phenytoin or inhibited by OCS or by severe liver disease.
Adult↗
Portal vein ligation selectively lowers hepatic cytochrome P450 levels in rats.
In rats, surgical creation of a portacaval shunt leads to hepatic atrophy and lowered levels of cytochrome P450, the key component of liver enzymes involved with drug metabolism. These effects are largely attributable to diversion of portal blood away from the liver and not to decreased hepatic blood flow. The present study has established a simpler model of portal blood diversion in order to examine the role of portal blood constituents in the regulation of hepatic cytochrome P450. Portal vein ligation was performed on male Wistar rats in which portasystemic anastomoses had been produced by subcutaneous transposition of the spleen. Portal vein ligation resulted in portal hypertension, as evidenced by splenomegaly, and in hepatic atrophy. In liver of rats with portal vein ligation, microsomal cytochrome P450 levels were significantly less than in sham-operated control rats, but cytochrome b5, NADPH-cytochrome c reductase, and glucose-6-phosphatase were unaltered. The activities of four mixed function oxidases also were reduced significantly in the liver of rats with portal vein ligation, the changes being greatest for ethylmorphine N-demethylase, a prototype substrate for the phenobarbital-inducible isoenzyme of cytochrome P450. In contrast, the activity of microsomal heme oxygenase, the rate-limiting step in catabolism of heme to bilirubin, was enhanced after portal vein ligation. Experiments in pair-fed rats showed that the changes observed in liver from rats with portal vein ligation could not be attributed to caloric deprivation. Administration of phenobarbital increased liver mass, cytochrome P450 levels, and mixed function oxidase activities both in rats with portal vein ligation and in controls, indicating that the liver of the ligated rats retained considerable protein synthetic capacity. It appears that hepatic atrophy and lowering of cytochrome P450 levels that follow portal vein ligation are consequences of altered exposure of the liver to factors normally present in portal blood, and that the same alterations may also enhance heme oxygenase activity.
Animals↗