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Biomedical subjects

G C Farrell

Publications and source records attributed to G C Farrell.

At least 145 records · Page 8Linked to original sources
PubMed1982

Crigler-Najjar Type 1 syndrome: absence of hepatic bilirubin UDP-glucuronyl transferase activity and therapeutic responses to light.

A 16-year-old boy with severe congenital unconjugated hyperbilirubinaemia is described in whom mental retardation occurred as an isolated neurological deficit. The diagnosis of Crigler-Najjar type 1 syndrome was supported by an extreme and persistent elevation of serum unconjugated bilirubin (650 mumol/l), failure of administered phenobarbitone to lower serum bilirubin concentration and family history of a similarly affected sibling. Hepatic bilirubin UDP-glucuronyl transferase activity determined in vitro by a sensitive new enzyme assay was found to be absent using bilirubin or bilirubin monoglucuronide as substrate. Phototherapy for 12 hours each night produced a partial but highly significant reduction in serum bilirubin concentration, which was not influenced further by the administration of cholestyramine.

Adolescent↗
PubMed1981

Cytochrome P-450 heme moiety. The specific target in drug-induced heme alkylation.

Exogenously administered heme is incorporated into rat hepatic cytochrome P-450 in vivo (Correia, M. A., Farrell, G. C. Schmid, R. S., Ortiz de Montellano, P. R., Yost, G. S., and Mico, B. A. (1979) J. Biol. Chem. 254, 15-17). This was demonstrated in allylisopropylacetamide (AIA)-treated rats by the formation of a radioactive adduct derived from the porphyrin of the administered [3H]heme and AIA. Formation of such adducts requires catalytic participation of cytochrome P-450 in oxidative metabolism of AIA to an active species which subsequently alkylates the prosthetic heme moiety of the cytochrome. These results suggested that the exogenous heme had been incorporated prosthetically into cytochrome P-450 prior to generation of the adduct. However, the possibility remained that a minute portion of the inactivating AIA-species escaped the catalytic site of the generating hemoprotein and alkylated the nonprosthetically bound isotopic heme. To examine this critical possibility, we have employed a chemical derivative of heme which binds to the microsomal membrane. Although this heme derivative is a structurally suitable target for attack by the inactivating drug species, we found that it was unsuitable for incorporation into the prosthetic site of cytochrome P-450. The findings of this study provide irrefutable evidence that the label recovered in drug-porphyrin adducts is derived exclusively from radioactive heme incorporated prosthetically into cytochrome P-450. Drug-porphyrin adducts can therefore be used as reliable probes to follow the transfer of heme from the hepatic "free" heme pool into cytochrome P-450.

Alkylation↗
PubMed1981

Heme enhances hexobarbital metabolism in perfused rat liver after drug-mediated destruction of cytochrome P-450.

During mixed-function oxidation of allylisopropylacetamide (AIA), autocatalytic destruction of hepatic cytochrome P-450 leads to retarded elimination of this agent. After AIA-mediated destruction of cytochrome P-450, exogenously administered heme that has entered liver cells is directly incorporated into cytochrome P-450. This raises the hepatic content of this hemoprotein, enhances the activity of mixed-function oxidases and accelerates hepatic clearance of the inactivating agent, AIA. We have studied the metabolic consequences of these phenomena for the disposition of hexobarbital coadministered with AIA in the isolated perfused rat liver. AIA decreased perfusate fractional disappearance of hexobarbital by approximately 80%. This was attributable to destruction of cytochrome P-450 rather than to competitive inhibition of hexobarbital metabolism, since by increasing the molar ratio of hexobarbital to AIA in perfusate, hexobarbital elimination was not enhanced. Heme administered after AIA significantly accelerated hexobarbital disappearance from the perfusate, reflecting increased hexobarbital metabolism by reconstituted cytochrome P-450. In the absence of prior destruction of cytochrome P-450 by AIA, heme failed to alter the rate of hexobarbital elimination. These findings demonstrate that drug-mediated destruction of cytochrome P-450 results in impaired hexobarbital metabolism, which is reversible by administration of heme. Heme infusion may be useful in treatment of patients poisoned with drugs that destroy hepatic cytochrome P-450.

Allylisopropylacetamide↗
PubMed1980

Structural and functional reconstitution of hepatic cytochrome P-450 in vivo. Reversal of allylisopropylacetamide-mediated destruction of the hemoprotein by exogenous heme.

After the heme moiety of hepatic cytochrome P-450 in rats had been destroyed by allylisopropylacetamide (AIA), intravenously injected heme significantly increased the cytochrome P-450 content and mixed function oxidase activity of liver microsomes. (The term "heme" is used throughout this paper for iron protorphyrin IX, irrespective of its redox state). In the absence of AIA treatment, heme administration failed to elicit these effects. The heme-mediated increase of cytochrome P-450 was most pronounced in phenobarbital-pretreated rats (46%), but was detectable also in 3-methylcholanthrene-pretreated (6%) and in untreated animals (7%). Restoration of mixed function oxidase activity by heme appeared to depend on reconstitution of cytochrome P-450 and was greatest for oxidases whose activity is stimulated by phenobarbital. Under optimal experimental conditions, heme enhanced the residual activity of ethylmorphine N-demethylase 3-fold when 92% of the initial enzyme activity had been destroyed by AIA. Reconstitution of cytochrome P-450 was dependent on the relative amount of cytochrome P-450 destroyed by AIA and on the dose of heme administered. Formation of holocytochrome P-450 appeared to be independent of apoprotein synthesis as it was unaffected by cycloheximide. Thus, reconstitution of cytochrome P-450 following AIA-mediated destruction of its original prosthetic heme reflects direct incorporation of administered heme into residual apoprotein in the endoplasmic reticulum. These findings demonstrate that exogenous heme can partially restore the structure and function of hepatic cytochrome P-450 following its drug-mediated destruction.

Acetamides↗
PubMed1980

Alterations of drug metabolism in rats exposed to cigarette smoke.

In male rats exposed to cigarette smoke, antipyrine clearance was enhanced to the same extent as has been observed in human cigarette smokers. The activity of aryl hydrocarbon hydroxylase, a representative microsomal mixed function oxidase, was increased significantly in lung and kidney of smoke-exposed rats compared with controls. The activity of this enzyme in the liver, however, was not altered by cigarette smoke. Although aryl hydrocarbon hydroxylase activity in extrahepatic tissues was significantly enhanced after cigarette smoke exposures, the total drug metabolizing capacity of these tissues remained trivial compared with that of the liver. Hence, extrahepatic drug metabolism is unlikely to account for enhanced antipyrine elimination in cigarette smokers. The present study has established an animal model for studying the changes produced by cigarette smoke which result in enhanced drug metabolism in man.

Animals↗
PubMed1979

Incorporation of exogenous heme into hepatic cytochrome P-450 in vivo.

Parenteral administration of [3H]heme to allylisopropylacetamide-treated rats resulted in the formation of a radiolabeled allylisopropylacetamide-porphyrin adduct in the liver, which was isolated and purified. Since formation of this adduct requires the heme moiety of a functional cytochrome P-450 species, our findings indicate that exogenously supplied heme had been incorporated into the hepatic microsomal hemoprotein. Moreover, they suggest that exogenously supplied heme readily gains access to an "unassigned" heme pool, which provides heme for cytochrome P-450 formation.

Allylisopropylacetamide↗
PubMed1979

Drug metabolism in liver disease: activity of hepatic microsomal metabolizing enzymes.

The concentration of cytochrome P-450 and activities of the microsomal enzymes aryl hydrocarbon hydroxylase and ethylmorphine demethylase were measured in hepatic tissue obtained at biopsy from 69 patients. Antipyrine half-life (AP t1/2) was measured simultaneously as an in vivo marker of drug metabolism. Values for each index of the drug-metabolizing system varied greatly, but the mean values in groups of patients with mild hepatitis or inactive cirrhosis did not differ significantly from those of controls. Hepatic cytochrome P-450 content and aryl hydrocarbon hydroxylase activity were lower in patients with severe hepatitis or active cirrhosis than in controls, but ethylmorphine demethylase activity was unchanged in the patients. Drug ingestion was associated with enhancement of drug-metabolizing enzymes in all patients but those with severe liver disease; ethylmorphine demethylase activity was enhanced proportionately more than aryl hydrocarbon hydroxylase activity or cytochrome P-450 concentration. The observation that aryl hydrocarbon hydroxylase and ethylmorphine demethylase activities are influenced to a different extent by liver disease and also by drug ingestion indicates functional heterogeneity of the hepatic microsomal drug-metabolizing system in man. Correlations between t1/2 and hepatic drug oxidases were weak, even when allowance was made for variation in liver size. Thus, the rate of drug metabolism in vivo assessed by measuring AP t1/2 does not appear to be closely related to the activity of some hepatic drug-metabolizing enzymes.

Antipyrine↗
PubMed1979

Enhancement of hepatic drug metabolism by glutethimide in patients with liver disease.

A controlled study of the effects of glutethimide on antipyrine metabolism was performed to ascertain how patients with varying degrees of liver damage responded to microsomal enzyme inducing agents. The administration of 250mg glutethimide daily for one week resulted in significant enhancement of antipyrine metabolism in 4 patients with compensated cirrhosis and 5 patients with features of hepatic failure as well as 7 control subjects without liver disease. Even patients with very severe liver disease did undergo microsomal enzyme induction. Changes in antipyrine half-life after glutethimide were directly proportional to the original antipyrine half-life so that the greatest absolute alterations due to enzyme induction occurred in patients with the most severely impaired hepatic function. These results indicate that not only is antipyrine metabolism severely impaired in patients with liver failure, but elimination rates are markedly altered by enzyme inducing agents. Thus, although these results cannot be extrapolated to all inducers of hepatic microsomal enzymes nor to all drugs metabolized by microsomal oxidases, it is suggested that safe and effective management of drug therapy in these patients requires measurement of plasma levels.

Adult↗
PubMed1978

Drug metabolism in liver disease. Identification of patients with impaired hepatic drug metabolism.

Antipyrine half-life (AP t1/2) was measured in 62 patients with, and 10 control patients without, liver disease to ascertain possible factors which may be useful in identifying patients with abnormal drug metabolism. Antipyrine metabolism was normal or marginally impaired in patients with compensated cirrhosis or acute hepatitis, whereas it was frequently abnormal in those with chronic active hepatitis or advanced alcoholic liver disease. A high degree of correlation was found among AP t1/2 and prothrombin time, hepatic encephalopathy, and ascites. Of patients with severely impaired drug metabolism, 80% had one or more of these features. The severity of histological changes in liver biopsies was of additional help in predicting impaired drug metabolism. Concurrent drug ingestion enhanced antipyrine metabolism in most patients with liver disease as well as in control patients. Inadequate diet was associated with prolongation of AP t1/2, but other environmental factors such as alcohol ingestion, cigarette smoking, and coffee consumption did not affect rates of drug metabolism in patients with liver disease. Consideration of all of the above factors allows qualitative predictions of the rate of hepatic drug metabolism in patients with liver disease, as assessed by the AP t1/2.

Acute Disease↗
PubMed1977

Abnormal liver function in chronic hypervitaminosis A.

A case of chronic hypervitaminosis A is reported in a 57-year-old woman who took vitamin preparations for alopecia. Liver biopsy of the patient showed both an increase in the number and size of fat-storing cells on light microscopy and rapidly fading green autofluorescence of vitamin A. Electron microscopy confirmed the presence of engorged fat-storing cells in the space of Disse and minor toxic changes in hepatocytes. This case illustrates the early hepatic changes of chronic hypervitaminosis A and indicates a need for restriction of sales of vitamin preparations.

Biopsy, Needle↗
PubMed1976

Enhanced drug metabolism in cigarette smokers.

The effect of cigarette smoking on salivary antipyrine disappearance rate, and as an index of hepatic drug metabolism, was studied in 42 healthy subjects. Antipyrine half life was significantly shorter in smokers compared with non-smokers. To determine whether this difference was due solely to tobacco consumption eight subjects were restudied two months after they stopped smoking. The mean antipyrine disappearance rate in this group increased by 23% in contrast to that of a control group, which did not alter. Cigarette smoking contributes to the considerable variation in interindividual rates of drug metabolism.

Adolescent↗
PubMed1976

Fanconi's familial hypoplastic anaemia with some unusual features.

A case of Fanconi's familial hypoplastic anaemia is described in a 48-year-old woman who had the usual haematological and constitutional abnormalities of this condition. Chromosomal studies on peripheral blood lymphocytes and direct marrow preparations demonstrated the chromosomal breaks previously described. The age of the patient and a congenital abnormality of breast development were unusual features, while the discovery of a benign liver tumour at necropsy is of interest, as the patient had received therapy with oxymetholone.

Abnormalities, Multiple↗
PubMed1976

Chronic granulomatous hepatitis.

Three cases are described in which a chronic relapsing febrile illness was associated with granulomas in the liver. None of the known causes of hepatic granulomas was present in these patients. In two cases there was clinical improvement after corticosteroid treatment and this was associated with resolution of the histological changes on liver biopsy. These three cases support the concept that chronic granulomatous hepatitis of unknown aetiology is a distinct entity.

Aged↗
PubMed1975

Androgen-induced hepatoma.

Three cases of hepatocellular carcinoma are reported in young men who had been taking androgenic-anabolic steroids. The tumours were histologically similar to those described in previous reports. The tumour progressed slowly in two patients during four and seven years of observation, but in the latter bony metastases occurred. In two patients the tumours regressed after administration of the drug was discontinued. These cases strengthen the evidence that exogenous androgenic-anabolic steroids may produce liver tumours. The use of these drugs should be confined to serious conditions in which they are known to be effective. Biochemical tests of liver function and serum alphs-fetoprotein estimation are not useful as screening-tests for hepatoma in patients taking androgens, and regular isotopic liver-scanning is recommended.

Adult↗