Animal Steroid Metabolism

Animal Steroid Metabolism.—The reduction of the A -double bond of cholesterol has already been discussed for plants. A similar process occurs in animals. Oxidation at C-3 is followed by an isomerisation to give the conjugated 4-en-3-one system. In rat livers a substantial isotope effect is observed when either the 

Nakano, C. Takemoto, H. Sato, and B. I. Tamaoki, Biochim. Biophys. Acta, 1968, 152, 186 C. Takemoto, H. Nakano, H. Sato, and B. I. Tamaoki, Biochim. Biophys. Acta, 1968, 152, 749. 

The oxidation of androst-4-en-3,17-dione (95 R = Me) to estrone (97) has been studied. Dehydrogenation to give androstadiendione (96 R = Me) involves the loss of the 1 - and 2j6-protons. Hydroxylation at C-19 may occur before or after the dehydrogenation. Most of the radioactivity of [19R- H]-androst-5-ene-3) ,17, 19-triol (95 R = CH20H,3) -0H) was recovered from formic acid while with the (19S)-isomer most of the tritium was in the water. This means that a stereospecific oxidation to the 19-oxo compound (95 R = CHO, 3 -OH) is followed by elimination of formic acid.  

Three distinct methods have been demonstrated for the cyclisation of squalene. Although most triterpenoids follow a similar route to lanosterol [(7)— (71)— (72) (73)] the 3-desoxytriterpenoids such as femene (98) are formed from squalene (7) not from 2,3-oxidosqualene (71). Presumably a proton-initiated cyclisation is followed by elimination of a hydrogen atom, with, or without, rearrangement of the carbonium ion . When [2- C,3R,4R- H]mevalonic acid 

Tetrahymanol (99) shows a variant process whereby the carbonium ion from proton-initiated cyclisation of squalene (7) is quenched by the medium. Again 

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Inevitably the study of steroid metabolism in infancy has had to be delayed until suitable techniques were available. Crystallographic techniques initially used for isolating steroids from adult and animal material were not applicable since considerable amounts of tissue or urine would be required. The early solvent partition and adsorption techniques involving countercurrent distribution and column chromatography could have been applied, but since considerable labor would have been involved and no gross difference from the adult pattern of steroid metabolism was suspected in infants, little work was done until the availability of paper and thin-layer chromatography greatly improved the feasibility of study. 

Variability in patterns of drug metabolism has been recognized for some time, even before the discovery of P450s. For instance, the phenomenon of pharmacogenetic variation had been identified by the 1950s and the early work of Remmer showed the influence of barbiturates upon drug metabolism. Further, a number of congenital defects in steroid metabolism were known and some could be attributed to alterations in specific hydroxylations. Much of the subsequent work on inducibility has been done in experimental animal models and later, cell culture. 

All foodstuffs of animal origin contains natural sex steroids at varying concentrations depending on the kind of tissue, species, gender, age, and physiological stage of the animal. Estradiol-17P is the most potent estrogen in animals and metabolized to estrone or estradiol-17a that are... 

Aquatic organisms, such as fish and invertebrates, can excrete compounds via passive diffusion across membranes into the surrounding medium and so have a much reduced need for specialised pathways for steroid excretion. It may be that this lack of selective pressure, together with prey-predator co-evolution, has resulted in restricted biotransformation ability within these animals and their associated predators. The resultant limitations in metabolic and excretory competence makes it more likely that they will bioacciimiilate EDs, and hence they may be at greater risk of adverse effects following exposure to such chemicals. 

It was known as early as 1927 that the adrenal glands of mammalian species secrete a series of substances essential to the survival of the individual. The hormonal nature of these secretions was suggested by the observation that extracts of the adrenal gland and more specifically of the outer portion of that organ (cortex) would ensure survival of animals whose adrenals had been excised. By 1943 no fewer than 28 steroids had been isolated from adrenal cortical extracts. These compounds were found to be involved in the regulation of such diverse and basic processes as electrolyte balance, carbohydrate metabolism, and resistance to trauma, to name only a few. 

It is difficult to reconcile the unique chemical structure of tetrodotoxin with that of an animal product. Its structure is not related to that of other animal products by any readily recognized biosynthetic scheme. It is not a terpenoid, not obviously formed from amino acid or carbohydrate units, and apparently not constructed from acetate or propionate units. Nor does it resemble any of the various plant alkaloid patterns. It thus appears to be a very unlikely animal product to result from known biogenetic pathways. In this connection the metabolic incorporation of radioactive precursors using torosa and ]C. granulosa salamanders was studied by Shimizu et al. (47). They observed significant isotopic incorporation into amino acids and steroid metabolites, but they found no such incorporation associated with tetrodotoxin. 

Several substances alter the toxicity of chloroform in animals— most probably by modifying the metabolism to a reactive intermediate. Factors that potentiate chloroform s toxic effects include ethanol, polybrominated biphenyls, steroids, and ketones. Disulfiram, its metabolites, and a high-carbohydrate diet... 

In the rat, development to adult levels of activity takes about 30 days after which levels decline toward old age. In humans, however, hydroxylase activity increases up to the age of 6 years, reaching levels greater than those in the adult, which only decrease after sexual maturation. Thus the elimination of antipyrine and theophylline was found to be greater in children than in adults. It should be noted, however, that proportions of isoenzymes may be very different in neonates from the adult animal, and the development of the isoenzymes may be different. Thus, in the rat there seem to be four types of development for phase 1 metabolizing enzymes linear increase from birth to adulthood, type A (aniline 4-hydroxylation) low levels until weaning, then an increase to adult levels, type B (N-demethylation) rapid development after birth followed by rapid decline to low levels in adulthood, type C (hydroxylation of 4-methylcoumarin) and rapid increase after birth to a maximum and then decline to adult levels, type D. Patterns of development may be different between sexes as well as between species. For example, in the rat, steroid 16-a-hydroxylase activity toward androst-4-ene-3,17-dione develops in type B fashion in both males and females, but in females, activity starts to disappear at 30 days of age and is undetectable by 40 days. It seems that the monooxygenase system develops largely as a unit, with the rate dependent on species and sex of the animal and the particular substrate. 

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