Teoría del captador solar de placa plana

It has been known for some time that FMO activities are generally highest in the liver and that expression of FMO activity in certain tissues is under the influence of the endocrine (143) and nutritional status (144) of the animal. Thus, FMO activity and/or amounts have been demonstrated to alter as a function of sex, age, oestrus cycle and pregnancy, and to be influenced by dietary conditions. However, FMO is not inducible by the classical cytochrome P450 inducers, such as phénobarbital, poly cyclic aromatic hydrocarbons, ethanol or macrolide antibiotics (145). Ascorbic acid-deficient guinea pigs reportedly have only 55% of hepatic FMO activity compared to ascorbic acid-adequate animals (144) and guinea pigs fed a calorie-restricted diet (leading to 10-15% weight loss) show a 77% increase in hepatic FMO activity, as measured by the rate of A-oxidation of A’,A^-dimethylaniline (146). Clearly, findings such as this, if similar in humans, would suggest that the nutritional state of individuals may have a bearing on the metabolism of drugs and pollutants. Dietary xenobiotics appear to influence FMO activity in the rat liver, as animals maintained on total parenteral nutrition for seven days (i.e. on a diet completely lacking in xenobiotics) show a 75-80% decrease in hepatic FMO activity (147). Similar

studies, in which rats were fed a synthetic diet for 1 week, showed a significant drop in FMO activity, as measured by the rate of ethyl-methyl-suiphide S-

oxygenation (148) and trimethylamine A^-oxygenation (149) (two selective functional markers for FMO activity). Results such as this raise interesting questions as to the impact of dietary constituents on hepatic FMO activity. Ziegler and colleagues have suggested that one or more organic nitrogen- or sulphur-containing xenobiotic(s) present in ordinary foodstuffs of plant origin yet absent from synthetic preparations are responsible for the induction of hepatic FMO, and Ziegler has suggested that FMO activity is already maximally induced in animals fed on commercial rat chow (24). It comes to mind what, if any, implications these findings may have if extrapolated to humans. Calorie restriction, adequate ascorbate intake and a diet rich in plant material are all correlated with a reduced risk of numerous so-called ‘western diseases’ in man, including cancers, cardiovascular disease, diabetes and other diseases associated with ageing. Only further research will establish whether diets common in the industrialized nations render populations prone to a reduced level of FMO activity and whether this has implications in health and disease. (150).

Sex related differences in the concentration or enzymatic activity of FMO have been observed in rats, mice and rabbits (102). Gender related differences for mouse liver FMO appear to be due to testosterone repression of the hepatic enzyme (151, 152). Rat liver FMO levels, on the other hand, appear positively regulated by testosterone and to be repressed by oestradiol (153). Oestradiol also seems to play a role in determining the relative contribution of FMO in the 5-oxygenation of methoxyphenyl 1,3-dithiolane observed in rat liver microsomes (143). Testosterone treatment of female CF-1 mice reduces FMO activity in the liver but not in the kidney (151). Administration of dexamethasone to Sprague-Dawley rats results in a 98% drop in hepatic FMO levels in males whereas in females hepatic levels remain unchanged (154). Devereux and Fonts were the first to document higher FMO activity in rabbit lung microsomes during pregnancy (through measurement of N^JsT-

dimethylaniline AT-oxidation) and the responsiveness of FMO activity in rabbit lung to administration of glucocorticoids (155). Although changes in the hormonal milieu during late gestation appear responsible for induction of FMO in rabbit lung, these same changes appear not to affect hepatic FMO levels in the rabbit, nor pulmonary or hepatic FMO levels in the mouse (78, 156). The levels of FMO in pregnant rabbit lung have since been shown in one study to be elevated at least five fold to 2-5nmol/mg of microsomal protein, or 12-30% of the total protein, exceeding the amounts of cytochrome P450 by approximately 5- to 10-fold and making them the predominant microsomal protein in this tissue

(74, 78, 157). Another study (156) reported that whilst FMO activity and amounts increased significantly in rabbit lung microsomes during the latter stages of pregnancy, at the same time these parameters remained unchanged in liver microsomes. Interestingly, the mineralocorticoid deoxycorticosterone mimics the affect of pregnancy on FMO activity in rabbit lung and administration of progesterone or dexamethosone (but not oestradiol or aldosterone) induces FM02 protein in rabbit lung (145, 156). FM02 mRNA and FM02 protein levels were reported to peak in the lungs of pregnant rabbits at days 15 and 28-31, correlating with elevations in progesterone and corticosterone plasma concentrations (38). Subsequent work, however, suggests that whilst FM02 in rabbit lung can be induced by either progesterone or glucocorticoids, enhanced FM02 expression during pregnancy is more closely related to progesterone levels (145). This contrasts with rabbit kidney, in which FM02 expression appears to be regulated by glucocorticoid levels rather than progesterone: FM02 protein levels in rabbit kidney peak at the same time as plasma cortisol is at its highest level during pregnancy (parturition) (145, 158). FM02 levels in the bladder, while lower than in lung and kidney, were increased by about two-fold during the 20-28th days of gestation (145). The levels of FMOl also appear increased during mid- and late- gestation in rabbit liver, probably also because of changes in the concentrations of progesterone and/or glucocorticoids, as administration of these steroids to male rabbits enhances FMOl mRNA levels four-fold (oestradiol and aldosterone had no effect, indeed, oestradiol pretreatment partially blocked the inducing effects of progesterone) (145). Similar experiments with CD-I mice have yielded contrasting data, with pregnancy resulting in no detectable alterations in FMO activity in lung but an increase in the placenta (159). In the case of sheep (which have been shown to have distinct hepatic and pulmonary FMO forms (160)), FMO may be induced in the liver but repressed in the lung of pregnant animals (160). In 1970, Heinze et al. (7) described a dramatic (twenty-fold) increase of A^,A^-dimethylaniline //-oxygenation in microsomes isolated from the corpora lutea of pigs in the later stages of their oestrus cycle. Furthermore, a five-fold induction in FMO activity has been demonstrated to occur in the placenta of pregnant mice (159). Gonadectomy experiments on young animals have further established the endocrinological influence that exists on regulation of FMO activity (151, 153). Diabetes can apparently induce FMO in mice (increase in imipramine N-oxidation) (161). Other researchers have demonstrated a diurnal regulation of female mouse liver FMO activity thought to be mediated by cortisol levels (124). Hypophysectomy of male rats has been shown to lead to a reduction in liver FMO activity (150). Administration of growth hormone or testosterone to these hypophysectomized rats only partially restored hepatic

FMO activities. In addition, the hypophysectomized male rats had enhanced FMO activity in the kidney but lowered activity in lung. Castration also reduced hepatic FMO activity in the male rat, though not to the same extent as hypophysectomy (150). In contrast, the hypophysectomized female rat showed no decrease in hepatic FMO activity: rather, there was evidence for an increase in activity (150). However, as with the male rats, hypophysectomy lowered lung FMO activity in females.

These findings have several implications. The plasticity of FMO expression suggests that the secondary side affects of certain drugs could be dependent in some cases on the extent of FMO expression in a given individual and the concomitant effects on xenobiotic metabolism that this would bring about (such interactions are well documented in the case of the cytochromes P450). Furthermore, it gives a rough indication of some of the upstream c/5-acting regulatory elements that could be expected to be found within FMO genes once appropriate sequence data have become available.