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3315S.Full.Pdf [CANCER RESEARCH (SUPPL.) 42, 3315S-3321 S. August 1982] 0008-5472/82/0042-0000$02.00 Basic Studies on Aminoglutethimide1 Hilton A. Salhanick Department of Population Sciences, Harvard School of Public Health, and Department of Obstetrics and Gynecology. Harvard Medical School, Boston. Massachusetts 02115 Abstract gical attempts to remove the naturally occurring steroidal hor mones on the other. The latter approach includes the admin Aminoglutethimide (AG), a bicyclic substance with two opti istration of tamoxifen, a target-receptor competitor of estro cally active isomers, inhibits the cholesterol side-chain cleav gens. Current thought is that AG acts by inhibiting steroido- age (SCO and aromatase systems by blocking the terminal genesis at the aromatase sites. cytochrome P-450s. AG interacts with these cytochromes to The purpose of this contribution is to review the actions of induce typical type II, low-spin spectra; the amount of spectral AG and attempt to relate them to therapeutic rationale. change correlates directly with the amount of enzymatic inhi bition. AG acts by preventing reduction of the cytochrome, an obligate step preceding oxygénationof substrate. The apparent Chemical Considerations K, of D(+ )-AG is about 2.5 times less than the K, of L(-)-AG in AG has 2 rings and an ethyl appendage (Chart 1). It resem inhibiting SCC and about 40 times less in inhibiting aromatase. bles glutethimide (Doriden), which lacks the amine. Since glu- The spectral Ks ratios of the D- and L-enantiomers for P-450scc tethimide has little or no antisteroidogenic activity, it follows and P-450a,omataseare2.5 and 5, respectively, in the presence that the amine is necessary for this biological activity. The of substrate. The slope of the substrate concentration versus sedative and other central nervous system-depressive activities inhibition curves is less than 0.1 and extends over 2 logarithmic of AG are most probably related to the piperidinedione ring, as units of substrate concentration. indicated by the common occurrence of the monoureide con By in vivo rabbit and rat assays for SCC, D-AG is 5 and 25 figuration in other sedatives in the glutethimide, barbiturate, times more potent than L-AG. In women, AG rapidly lowers and hydantoin series. These include thalidomide and cyclohex- estrogen and progesterone levels in the luteal phase of the imide, which do not inhibit SCC (4).3 The former is teratogenic menstrual cycle and in early pregnancy, eliciting a reflex and the latter blocks protein synthesis. They raise the suspicion release of luteinizing hormone in the luteal phase. In postmen- that AG may have a direct effect on cell reproduction or opausal, adrenalectomized, ovariectomized women, AG pre function. Studies with AG analogs indicate that few substances, vents the aromatization of administered androstenedione. including those with even minor modifications, are as potent as In inhibition studies in women, plasma steroid concentrations AG in the inhibition of SCC or aromatase. were inversely proportional to AG levels, which were about 20 Because it is likely that the amine interacts with the proto- to 30 /UM.This level of AG, which approximates the apparent porphyrin iron of the cytochrome P-450s involved, we have K¡sof the SCC and aromatase systems, causes a decrease in postulated that the aromatic ring "stacks" on the aromatic-like hormone levels of about 50%. porphyrin structure and that the remainder of the molecule assigns some specificity by its affinity to the apoprotein (9). If Introduction this is true, then the separation of antisteroidogenic properties AG2 has been a drug of promise for more than 2 decades. from central nervous system properties may not be achieved easily. Initially introduced as a promising anticonvulsant agent, it was Of more current significance is the fact that the therapeutic withdrawn from use in 1966 because of its antisteroidogenic drug currently available is a mixture of the D(+ )- and L(—)- actions. Casually labeled a substance wh'ch induced "medical adrenalectomy," AG was demonstrated to inhibit steroidogen- enantiomers. These isomers have markedly different biological properties and, in the opinion of this author, merit serious esis at the cholesterol SCC site (1 ). On the basis of the medical consideration for further individual study. adrenalectomy concept, it was tested as a possible therapeutic agent for metastatic breast cancer. This too has been modified Cytochrome P-450-linked Enzyme Systems conceptually; its role in the therapy of breast cancer is now attributed to its action as an aromatase inhibitor. AG inhibits 2 enzyme systems: cholesterol SCC and aroma The understanding of medicinal therapy of breast cancer is complicated by other paradoxes. "Effective" treatments have tase. The SCC system has been thoroughly studied in many species and under many experimental conditions. The side included treatment with large doses of estrogens, androgens, chain of cholesterol is removed by a series of 3 oxidation steps or progestational agents, on one hand, and medical and sur- requiring 3 mol of oxygen and 3 mol of NADPH. The 3 steroidal 1 Presented at the Conference "Aromatase: New Perspectives for Breast steps involve hydroxylations at positions 22 and 20 and sub Cancer." December 6 to 9, 1981. Key Biscayne, Fla. Work from this laboratory sequent cleavage between these carbon atoms with loss of was supported by USPHS Grant 10081 from National Institute of Arthritis, capryl aldehyde. The reaction occurs on the terminal enzyme Metabolism and Digestive Diseases. NIH, Research Contract NIH-70-2319 from the National Institute of Child Health and Human Development, and Grant PDT- of an electron transport chain, cytochrome P-450scc- 147 from the American Cancer Society. The enzyme has been purified, and its amino acid constitu- 2 The abbreviations are: AG, aminoglutethimide [3-<4-aminophenyl)-3-ethyl- 2.6-piperidinedione]; SCC, side-chain cleavage: LH, luteinizing hormone. 3 P. E. Graves, V. I. Uzgiris, and H. A. Salhanick. unpublished observations. AUGUST 1982 3315s Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1982 American Association for Cancer Research. H. A. Salhanick P-450(RED.)-CHOL. ICYTOCHROME P-450 •¿if PREQNENOLONE P-450(OX.) A Chart 2. Pathway for supplying reducing equivalents to support the conver sion of cholesterol (CHOL.ÃŒto pregnenolone. Electrons (e ) from NADPH are D(+)AMINOGLUTETHIMIDE L(-)AMINOQLUTETHIMIDE transported through flavoprotein reducíase (FP) to iron sulfur protein (ISP) to cytochrome P-450scc- Cholesterol is bound to cytochrome P-450scc in the oxidized (OX.) state. The complex is reduced (RED), and the substrate is oxidized to pregnenolone in 3 oxidative steps. The other product, capryl aldehyde, is not shown. elsewhere in this symposium (2), aromatase converts the A ring of a 19-carbon steroid such as testosterone or andro- stenedione to a phenolic estrogen such as estradiol or estrone. This system is microsomal and does not require a ferridoxin- like protein; electrons are transferred directly by a flavoprotein reducíase from NADPH to the terminal enzyme, presumably cytochrome P-450a,omataM- QLUTETHIMIDE PHENOBARBITAL Unfortunately, cytochrome P-450aromatasehasnot been puri fied. In fact, the evidence that aromatase is a cytochrome P- 450 is still somewhat circumstantial. Placenta! cytochrome P- 450aromaiase,themost commonly studied enzyme, does not have the affinity for carbon monoxide common to other cytochrome P-450S. Also, placental preparations appear to contain other microsomal P-450s as well as contamination by mitochondrial cytochrome P-450Scc- Therefore, interpretations based upon spectral and electron spin resonance data are not conclusive. Furthermore, since AG can inhibit enzymes other than cyto chrome P-450, this property cannot be utilized as proof of cytochrome P-450 involvement. Nevertheless, it is probable CYCLOHEXIMIDE that the enzyme linked to aromatizaron is a cytochrome P-450, Chart 1. Structure of AG and related substances. and, having expressed the caveat, we will make the assumption that aromatization is achieved by a cytochrome P-450aromatase lion has been determined (5, 6). It probably acts in an aggre system. gate form involving at least 4 units and possibly as many as 16 Using the better studied cytochrome P-450Scc as a model, for optimal activity in vitro. Whether this is the case in vivo is the sequence of molecular events involved in steroid oxidation not clear because it is almost impossible to duplicate, in recon is represented simply in Chart 2. Cholesterol associates with stituted systems, the hydrophobic arrangement of the enzymes cytochrome P-450 in the oxidized state to form the substrate- in the inner membrane of the mitochondrion. Nevertheless, enzyme complex. The heme is reduced by electrons from the under proper conditions, it can be demonstrated to have a electron transport system described above. This complex is turnover rate of about 20 nmol of cholesterol per mol cyto- now sensitive to interaction with available molecular oxygen chrome P-450 per min (5). and oxidation of substrate occurs rapidly. If carbon monoxide The heme group of cytochrome P-450scc is usually in the is present, it binds preferentially to the heme and inhibits the oxidized state. To function, it requires electrons transported by reaction. It should be noted that CO binds to this heme only in a ferridoxin-like protein (iron sulfur protein) which, in turn, the reduced state. The extent of CO-heme interaction can be receives its electrons from a flavoprotein reducíase. Finally, measured by the generation of a dramatic absorbance peak at the flavoprotein utilizes NADPH as an electron source. NADPH 450 nm. Most likely, the substrate remains at its site and is generated by reversed electron transport through the con undergoes 3 oxidation steps, but it is clear that conditions may ventional respiratory chain. Thus, cholesterol SCC is achieved be modified to favor the collection of intermediates. by a "multienzyme system," the terminal enzyme of which is Aromatase probably acts in a similar fashion although the cytochrome P-450Scc (Chart 2).
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