HEPATIC MICROSOMAL ENZYME INDUCTION AND ADRENAL CRISIS DUE TO o,p’DDD THERAPY FOR METASTATIC ADRENOCORTICAL CARCINOMA
R. V. HAGUE, W. MAY AND D. R. CULLEN
The Departments of Medicine, The District General Hospital, Barnsley, and The Royal Hallamshire Hospital, Sheffield, UK
( Received 6 December 1988; returned for revision 19 January 1989; finally revised 24 February 1989; accepted 2 March 1989)
SUMMARY
Two cases are described in which metastatic adrenocortical carcinoma asso- ciated with Cushing’s syndrome was treated with mitotane (o,p’DDD). The first patient had initially been treated by bilateral adrenalectomy and, whilst responding to mitotane biochemically and by remission of metastases, experi- enced repeated episodes of adrenal crisis requiring a substantial increase in steroid therapy. The second patient failed to respond to the drug, but evidence of hepatic enzyme induction was noted during its administration. It is suggested that hepatic microsomal enzyme induction can occur in association with treatment with mitotane and that this can lead to an increased destruction of exogenous steroid with clinical consequences.
o.p’-Dichlorodiphenyldichloroethane (o,p’DDD, mitotane), a derivative of the insecti- cide DDT, has long been recognized to be selectively toxic to adrenocortical cells (Nichols & Hennigar, 1957). Its use in the treatment of adrenocortical carcinoma in humans has resulted in a significant prolongation of survival time (Hutter & Kayhoe, 1966; Lubitz et al., 1973; Ostuni & Roginski, 1975). Although the drug has been shown to induce a selective necrosis of the adrenal cortex, it also alters the extra-adrenal metabolism of cortisol (Bledsoe et al., 1964). In this paper, a patient with metastatic adrenocortical carcinoma treated by bilateral adrenalectomy and mitotane therapy is presented, in whom exogenous steroid replacement therapy needed to be increased to unusually high levels which diminished only when mitotane therapy was withdrawn. The hypothesis that this phenomenon might be due to hepatic microsomal enzyme induction resulting in enhanced steroid destruction finds support in a second case treated with mitotane in whom evidence of enzyme induction was demonstrated.
Correspondence: Dr R. V. Hague, The Department of Medicine, Barnsley District General Hospital, Gawber Road, Barnsley S75 2EP, UK.
g/day
6
o,p’ DDD
0
1000
0.3
Plasma cortisol (nmol/l)
Dosage (mg/day)
Fludrocortisone
800
0
0
0
Betamethasone img/day
100
600
Hydrocortisone
Encephalopathy
0
400
Addisonian crises
200
?
0
$
:
Sep
Oct
Nov
Dec
Jan
Feb
Mar
Apr
June
July
Aug
Sept
1974
1975
METHODS
Plasma cortisol was measured in patient 1 by a competitive protein binding method (Murphy et al., 1963) and in patient 2 by a commercial radioimmunoassay kit supplied by CIS (UK) Ltd.
Plasma and salivary antipyrine were measured by high-pressure liquid chromato- graphy (Eichelbaum & Spannbrucker, 1977), with the modification of using a reverse- phase column (C18 micro-Bondapak, Waters Assoc. Ltd, Northwich, Cheshire) and a mobile phase of methanol: water 50: 50. The coefficient of variation of the assay was 2.5% at a concentration 10 µg/ml.
PATIENT 1
A 38-year-old woman presented in June 1974 with Cushing’s syndrome due to a right adrenocortical carcinoma. Following bilateral adrenalectomy, plasma cortisol levels remained elevated and subsequently chest X-rays revealed multiple small metastases in both lung fields with hilar gland enlargement.
Mitotane therapy was started in September 1974, in a dose of 0.5 g twice daily and increased over a period of 6 weeks to 6 g daily, given in 4 doses (Fig. 1). During mitotane therapy she was initally maintained on betamethasone 0.5 mg twice daily to avoid any possibility of an adrenal crisis whilst still permitting measurement of endogenous cortisol production.
During the first two months of mitotane therapy, maximal suppression of endogenous plasma cortisol levels was obtained without troublesome side-effects apart from a generalized erythematous macular rash which gradually disappeared despite continua- tion of treatment. After a further month the dose was reduced to 5 g daily because of marked anorexia, nausea, vomiting and diarrhoea. Later her finger nails became dystrophic and there was considerable scalp hair loss, but all these complications improved with the reduced dosage of mitotane and both hilar gland enlargement and the pulmonary metastases were undetectable on tomography within 2 months.
After 3 months’ treatment with mitotane the patient was admitted in severe adrenal crisis. The serum sodium was 116 mmol/l, serum potassium 6-5 mmol/l, blood urea
160
14
Hepatic enzymes (IU/L)
120
12
10
o,p’ DDD (g/day)
80
8
6
40
4
2
0
0
0
10
20
30
40
50
60
70
80
Time (days)
11.4 mmol/l and blood glucose 5.3 mmol/1. She responded rapidly to intravenous normal saline and hydrocortisone therapy. This was thought to be due to inadequate steroid replacement therapy since her husband confirmed her compliance. However, even after adding fludrocortisone in increasing dosage to 0.2 mg daily and substituting hydrocorti- sone 50 mg daily in divided dose for the betamethasone, three further episodes occurred. Subsequent episodes of adrenal crisis were prevented only when her maintenance therapy was increased to hydrocortisone 100 mg daily in divided dosage and fludrocortisone 0.3 mg daily.
It became necessary to stop mitotane in April 1975 as a result of an encephalopathy which quickly resolved. Plasma cortisol levels remained suppressed for several months before a rise which heralded a recurrence of metastatic disease from which she suddenly died. Autopsy revealed occlusion of the main pulmonary arteries by tumour tissue and thrombus which had originated from a recurrent tumour in the right adrenal bed which was extending into the right renal vein and into the inferior vena cava. The lungs and brain were histologically free of metastases.
PATIENT 2
In September 1982 a 63-year-old man presented with Cushing’s syndrome due to carcinoma of the left adrenal which involved the pedicle of the left kidney and para-aortic lymph nodes. The left adrenal and kidney were removed and a block dissection of the lymph nodes was carried out. Both his clinical progress and cortisol levels remained satisfactory until September 1983 when his Cushing’s syndrome returned together with radiological evidence of pulmonary metastases.
Treatment with mitotane was started in a dosage of 2 g daily steadily increasing to a maximum of 14 g daily over a period of 42 days (Fig. 2). Cortisol levels remained unaltered and the lung metastases increased in size and number. Secondaries appeared in the liver. Treatment with mitotane was discontinued after a total of 48 days both because of the obvious lack of response and drug side-effects. His appetite and weight, however, remained constant throughout this period. Metyrapone was given but with no benefit and
the patient died within 2 weeks. Autopsy revealed metastases in lymph nodes, lungs, spleen and liver. The right adrenal gland was atrophic.
During the period of observation liver function tests were monitored at regular intervals (Fig. 2). Gammaglutamyl transpeptidase steadily rose as the dose of mitotane was increased, only to fall rapidly as soon as the drug was stopped. Bilirubin, AST and ALT all remained normal except on one single occasion when both AST and ALT rose slightly, only to fall immediately to normal in spite of subsequent increases in the dosage of mitotane. Antipyrine half-life, measured when the dose of mitotane was at its greatest (plasma and saliva 6.79 and 6-49 h respectively) was substantially shorter than when measured prior to starting treatment with mitotane (9.64 and 8.25 h respectively).
DISCUSSION
Although mitotane prolongs the survival of patients with metastatic adrenocortical carcinoma when used either on its own (Bergenstal et al., 1959; Hutter & Kayhoe, 1966; Lubitz et al., 1973; Jarabak & Rice, 1981) or in combination with other drugs (Ostuni & Roginski, 1975), side-effects are common, with only some 17% of patients experiencing no ill effects (Lubitz et al., 1973). Our first patient made a very satisfactory clinical response with a dramatic resolution of the pulmonary metastases. This was achieved, however, at the expense of troublesome side-effects even with the relatively low dosage used. Whilst anorexia, nausea, vomiting and diarrhea are common, skin rashes and alopecia are also well documented (Lubitz et al., 1973) whilst encephalopathy is unusual (Danowski et al., 1964). In patients demonstrating a hormonal response the need for glucocorticoid replacement therapy should be anticipated (Schein, 1972) and, indeed, replacement doses of a mineralocorticoid are also frequently required (Hogan et al., 1978).
One of the most serious complications of therapy in this patient, however, was her tendency to development episodes of adrenal crisis while taking doses of exogenous steroids which would normally be considered adequate for replacement purposes (Besser & Edwards, 1972). It would appear that mitotane in some way increased the requirement for steroid replacement therapy, since a precipitating cause for adrenal crisis, namely an asymptomatic urinary infection, was found on only one occasion. Hepatic microsomal enzyme induction leading to enhanced steroid degradation is the most likely mechanism by which this phenomenon could be explained.
Organochlorine insecticides are known to induce microsomal enzymes (Street, 1969) and this causes accelerated metabolism of many substances. Mitotane, which is closely related chemically, shares this property (Kupfer & Peets, 1966; Street, 1969) and has been shown to increase cortisol metabolism in animals (Kupfer et al., 1964; Kupfer & Peets, 1966) and man (Southren et al., 1966a, 1966b) and warfarin in man (Cuddy & Loftus, 1986). Paradoxically, studies of the plasma disappearance rates of steroids in man during treatment with mitotane have revealed a prolonged half-life (t1/2) of injected cortisol (Southren et al., 1966b; Van Slooten et al., 1984) and a decreased t1/2 of dexamethasone (Van Slooten et al., 1984) although the clinical relevance of these studies is uncertain. Van Slooten et al. (1984), however, reported that four patients of their series of 34 with adrenocortical carcinoma treated with mitotane, developed signs, symptoms and
biochemical features of adrenal insufficiency during what would normally be considered to be adequate substitution therapy with dexamethasone (1 mg/day) and fludrocortisone (0.1 mg/day).
Under normal circumstances, cortisol is mainly metabolized to 17-hydroxycorticoids, but a small fraction is converted in the liver microsomes to the alternative excretory product 68-hydroxycortisol and this fraction is greatly increased during enzyme induction (Goldberg, 1980). It has been shown that treatment with mitotane results in an increase in the 6 B-hydroxylation of cortisol (Bledsoe et al., 1964; Fukushima et al., 1971; Pal, 1978). As a consequence, the proportion of cortisol excreted as tetrahydrocortisone is reduced and production of the more rapidly excreted polar metabolite 6 ß-hydroxycorti- sol is increased (Koide et al., 1985). There is some evidence from animal studies that 6 ß- hydroxycortisol is metabolically inactive (Kupfer et al., 1964). In normal subjects this rapid rate of corticosteroid metabolism would presumably be compensated by increased ACTH production, but clinical problems may arise when steroid availability is limited (Hunter, 1974), as illustrated by our first patient.
Although evidence of hepatic microsomal enzyme induction was not sought in our first patient, convincing evidence of this was revealed by studies in our second. A rise in the serum gamma-glutamyl transpeptidase, an hepatic microsomal enzyme, occurs in situations where hepatic microsomal enzyme induction is known to take place, for example during anticonvulsant therapy and chronic alcoholism (Whitfield et al., 1973; Goldberg & Martin, 1975; Goldberg, 1980). This was not measured in our first patient but, although our second failed to respond to treatment with mitotane by a reduction in plasma cortisol or a resolution in metastases, there was a sixfold increase in gamma- glutamyl transpeptidase which fell as soon as treatment with the drug was withdrawn. Since the day-to-day variation in serum gamma-glutamyl transpeptidase activity is only of the order of 10% (Whitfield et al., 1973) this change was felt to be significant. Neither patient was taking any other drug which could have resulted in enzyme induction. This finding was reinforced by the demonstration of a reduction in the plasma and salivary half-life of antipyrine, a test which has been considered the reference procedure for revealing microsomal enzyme induction (Goldberg, 1980). Although many environmen- tal factors such as diet, cigarette smoking (Krishnaswamy & Naidu, 1977), drugs (Stevenson, 1977), liver disease, thyroid disease (Park, 1982) and possibly anaemia (Desai et al., 1980) can affect antipyrine half-life, there was no evidence that these were relevant to the changes observed in this patient. It is probable that the cortisol production rate by the tumour on this occasion significantly exceeded the capacity of the induced liver enzymes for cortisol degradation; thus adrenal insufficiency was never provoked.
The hypothesis that enzyme induction can result in increased steroid requirements must be considered unproven on the basis of a study of enzyme induction in only one patient, but the associated clinical evidence from our first patient makes this highly probable and worthy of further investigation. o,p’DDD is useful in the treatment of metastatic adrenocortical carcinoma, but its somatic side-effects may be so severe as to merit its withdrawal. In spite of the fact that its adrenolytic effect has been shown to spare the zona glomerulosa (Nelson & Woodward, 1949; Nichols & Hennigar 1957) its action as an inducer of hepatic microsomal enzymes should alert the clinician to the possibility that unusually high doses of exogenous steroids, both of mineralocorticoids and of glucocorticoids, might be required for replacement therapy to allow for their enhanced destruction.
We would like to thank Dr V. Sanches Martinez for performing the antipyrine studies, Dr Colin Wilde for helpful advice and criticism and Mrs D. Grayson for typing the manuscript.
REFERENCES
BERGENSTALL, D.M., LIPSETT, M.B., MOY, R.H. & HERTZ, R. (1959) Regression of adrenal cancer and suppression of adrenal function in man by o,p’DDD. Transactions of the Association of American Physicians, 72, 341-350.
BESSER, G.M. & EDWARDS C.R.W. (1972) Cushings’ Syndrome. Clinics in Endocrinology and Metabolism (ed. A.S. Mason), 1, 451-490.
BLEDSOE, T., ISLAND, D.P., NEY, R.L. & LIDDLE, G.W. (1964) An Effect of o,p’DDD on the extra-adrenal metabolism of cortisol in man. Journal of Clinical Endocrinology, 24, 1303-1311.
CUDDY, P.G. & LOFTUS, L.S., (1986) Influence of mitotane on the hypoprothrombinemic effect of Warfarin. Southern Medical Journal, 79, 387-388.
DANOWSKI, T.S., SARVER, M.E., MOSES, C. & BONESSI, J.V. (1964) o,p’DDD therapy in Cushing’s Syndrome and in obesity with cushingoid changes. American Journal of Medicine, 37, 235-250.
DESAI, N.K., SHETH, U.K., MUCKLOW, J.C., FRASER, H.S., BULPITT, C.J., JONES, S.W. & DOLLERY, C.T. (1980) Anti-pyrine clearance in Indian villagers. British Journal of Clinical Pharmacology, 9, 387-394.
EICHELBAUM, M. & SPANNBRUCKER, N. (1977) Rapid and sensitive method for the determination of antipyrine in biological fluids by high pressure liquid chromatography. Journal of Chromatography, 140, 288-292.
FUKUSHIMA, D.K., BRADLOW, H.L. & HELLMAN, L. (1971) Effects of o,p’DDD on cortisol and 6 B-Hydroxycortisol secretion and metabolism in man. Journal of Clinical Endocrinology, 32, 192-200.
GOLDBERG, D.M. & MARTIN, J.V. (1975) Role of y-Glutamyl transpeptidase activity in the diagnosis of hepatobiliary disease. Digestion, 12, 232-246.
GOLDBERG, D.M. (1980) The expanding role of microsomal enzyme induction and its implications for clinical chemistry. Clinical Chemistry, 26, 691-699.
HOGAN, T.F., CITRIN, D.L., JOHNSON, D.M., NAKAMURA, S., DAVIS, T.E. & BORDEN, E.C. (1978) o,p’DDD (Mitotane) therapy of adrenal cortical carcinoma. Cancer, 42, 2177-2181.
HUNTER, J. (1974) Enzyme induction and medical treatment. Journal of the Royal College of Physicians of London, 8, 163-174.
HUTTER, A.M. & KAYHOE, D.E. (1966) Adrenal cortical carcinoma: results of treatment with o,p’DDD in 138 patients. American Journal of Medicine, 41, 581-592.
JARABACK, J. & RICE, K. (1981) Metastatic adrenal cortical carcinoma: prolonged regression with mitotane therapy. Journal of the American Medical Association, 246, 1706-1707.
KOIDE, Y., INOUE, S., MURAYAMA, H., KAWAI, K. & YAMASHITA, K. (1985) Effect of o,p’DDD on cortisol metabolism in Cushing’s syndrome of various etiology. Endocrinology Japon, 32, 615-624.
KRISHNASWAMY, K. & NAIDU, A.N. (1977) Microsomal enzymes in malnutrition as determined by plasma half life of antipyrine. British Medical Journal, 1, 538-540.
KUPFER, D., BALAZS, T. & BUYSKE, D.A. (1964) Stimulation by o,p’DDD of cortisol metabolism in the Guinea Pig. Life Sciences, 3, 959-964.
KUPFER, D. & PEETS, L. (1966) The effect of o,p’DDD on cortisol and hexobarbital metabolism. Biochemical Pharmacology, 15, 573-581.
LUBITZ, J.A., FREEMAN, L. & OKUN, R. (1973) Mitotane use in Inoperable adrenal cortical carcinoma. Journal of the American Medical Association, 223, 1109-1112.
MURPHY, B.E.P., ENGLEBERG, W. & PATTEE, C.J. (1963) Simple method of determination of plasma corticoids. Journal of Clinical Endocrinology and Metabolism, 23, 293-300.
NELSON, A.A., & WOODWARD, G. (1949) Severe adrenal cortical atrophy (cytotoxic) and hepatic damage produced in dogs by feeding 2, 2-bis (parachlorophenyl) -1, 1-dichloroethane (DDD or TDE). Archives of Pathology (Chicago), 48, 387-394.
NICHOLS, J. & HENNIGAR, G. (1957) Studies on DDD, 2, 2-bis (parachlorophenyl) -1, 1-dichloroethane. Experimental Medicine and Surgery, 15, 310-316.
OSTUNI, J.A. & ROGINSKI, M.S. (1975) Metastatic adrenal cortical carcinoma: documented cure with combined chemotherapy. Archives of Internal Medicine, 135, 1257-1258.
PAL, S.B. (1978) Progress in endocrinology and metabolism. 6-Hydroxylation of cortisol and urinary 6 B-Hydroxycortisol. Metabolism, 27, 1003-1011.
PARK, B.K. (1982) Assessment of the drug metabolism capacity of the liver. British Journal of Clinical Pharmacology, 14, 631-651.
SCHEIN, P.S. (1972) Chemotherapeutic management of the hormone-secreting endocrine malignancies. Cancer, 30, 1616-1626.
SOUTHREN, A.L., TOCHIMOTO, S., STROM, L., RATUSCHNI, A., Ross, H. & GORDON, G. (1966a) Remission in Cushing’s syndrome with o,p’DDD. Journal of Clinical Endocrinology, 26, 268-278.
SOUTHREN, A.L., TOCHIMOTO, S., ISURUGI, K., GORDON, G.G., KRIKUN, E. & STYPULKOWSKI, W. (1966b) The effect of 2, 2-bis (2-chlorophenyl-4-chlorophenyl)-1, 1-dichloroethane (o,p’DDD) on the metabolism of infused cortisol -7-3H. Steroids, 7, 11-29.
STEVENSON, I.H. (1977) Factors influencing antipyrine elimination. British Journal of Clinical Pharmacology, 4, 261-265.
STREET, J.C. (1969) Organochlorine insecticides and the stimulation of liver microsome enzymes. Annals New York Academy of Sciences, 160, 274-290.
VAN SLOOTEN, H., MOOLENAAR, A.J., VAN SETERS, A.P. & SMEENK, D. (1984) The treatment of adrenocortical carcinoma with o,p’DDD: prognostic simplications of serum level monitoring. European Journal of Cancer and Clinical Oncology, 20, 47-53.
WHITFIELD, J.B., Moss, D.W., NEALE, G., ORME, M. & BRECKENRIDGE, A. (1973) Changes in plasma y-glutamyl transpeptidase activity associated with alteration in drug metabolism in man. British Medical Journal, 1, 316-318.