Raymond H. Menard

Studies on the mechanism of the lung toxicity of paraquat: Comparison of tissue distribution and some biochemical parameters in rats and rabbits

Abstract After iv injection of [14C]paraquat (20 mg/kg) tissue localization was preferential in lungs of rats as well as rabbits although the latter did not show any histopathologic or biochemical signs of lung damage. No preferential subcellular localization of [14C]paraquat was found in lungs of either species, but all subcellular levels decreased more rapidly in the rabbit than in the rat. [14C]Paraquat was not covalently bound to tissue macromolecules. In vitro measurements of lipid peroxidation, H2O2 formation and lung lysosomal stability failed to account adequately for the lung damage in the rat.

Spironolactone and Endocrine Dysfunction

Therapy with spironolactone is often associated with estrogenlike side-effects, including impotence and gynecomastia in men and menstrual irregularity in women. Several possible mechanisms by which spironolactone could cause these side-effects have been identified. Spironolactone has been shown to affect both gonadal and adrenal steroidogenesis, to elevate plasma gonadotrophin levels in children, and to act as an antiandrogen at the target tissue level. This conference presents a discussion of how these effects might interact to produce the endocrine side effects associated with spironolactone therapy.

Active products of fetal drug metabolism

Theoretical relationships between the activities of placental and fetal enzymes and their ability to perturb the steady‐state tissue levels of drugs have been calculated. Although the calculations suggest that the activities of the enzymes that metabolize desipramine and 3,4‐benzpyrene in human placentas and fetuses may be high enough to decrease the steady‐state concentrations of these substances, the rates of metabolism of most drugs are probably too slow to affect the fetal levels of most lipid‐soluble compounds. It is also probable that the rate of bromobenzene metabolism by cytochrome P‐450 enzymes in fetal liver is too slow to cause liver necrosis caused by this toxicant. Nevertheless, it is possible that enzymes that catalyze the reduction of nitro compounds, such as nitrofurazone, to hydroxylamino derivatives may mediate various drug toxicities in fetuses.

The effect of the administration of spironolactone on the concentration of plasma testosterone, estradiol and cortisol in male dogs

The effect of the administration of spironolactone, deacetylspironolactone, aldadiene or soldactone on the concentration of plasma testosterone, estradiol, and cortisol was examined in male dogs. Decreases of 60 to 75% in plasma testosterone and estrodiol occur only at high doses (100 mg/kg) of spironolactone or deacetylspironolactone but not at low doses of spironolactone (5 to 10 mg/kg); they occur concomitantly with similar decreases of androgen formation by the testis. No decreases were detected with aldadiene or soldactone. Treatment of dogs with spironolactone (100 mg/kg) also lowered by 50 to 65% the concentration of cortisol in adrenal venous plasma.

Effect of chronic treatment with phenobarbital or 3-methylcholanthrene on the male reproductive system in rats

Abstract Treatment of rats for 4 weeks with phenobarbital (PB) did not inhibit the growth of the seminal vesicles, nor did it affect the biosynthesis of testosterone by testis microsomes. Moreover, neither the concentration of cytochrome p-450 or the 17 α-hydroxylase activity in testis microsomes were affected. In contrast, treatment with 3-methylcholanthrene (3-MC) for 4 weeks markedly decreased the weights of the seminal vesicles. The decrease was probably related to an impairmant of testosterone formation in the gonads, since testosterone biosynthesis as well as the concentration of cytochrome p-450 and the activity of 17 α-hydroxylase in testis microsomes were significantly decreased in the 3-MC treated rats. No histopathological changes were seen in testes from any of the PB or 3-MC treated rats.

Carbon-13 nuclear magnetic resonance studies of spironolactone and several related steroids

The 13C chemical shifts for all the carbon atoms is spironolactone have been assigned. Assignments for nine additional steroids which include the C-7 beta isomer of spironolactone, its C-7 thiol hydrolysis product, the 7 alpha-thioacetate derivative of testosterone and its thiol hydrolysis product are also reported.

OVARIAN ARYL HYDROCARBON HYDROXYLASE ACTIVITY AND OOCYTE DESTRUCTION

Publisher Summary This chapter discusses the ovarian aryl hydrocarbon hydroxylase activity and oocyte destruction. The polycyclic aromatic hydrocarbons (PAHs) destroy primordial oocytes in the ovary of inbred C57BL/6N(B6) and DBA/2N(D2) mice and Sprague-Dawley (SD) rats with significant differences in rate and sensitivity. PAHs are not toxic, mutagenic, or carcinogenic but require metabolic activation to reactive electrophilic species before adverse effects are observed. Although metabolic activation is necessary for PAH toxicity, mutagenicity, and carcinogenicity, it is not sufficient because it does not reflect the ability of the organ or tissue to detoxify the reactive metabolite or repair subcellular damage. The rodent ovary may provide a system in which the relationships between toxication, detoxication, and repair can be explored in a quantitative fashion through oocyte number. This system takes advantage of the fact that oocytes are identified and counted in standard histological preparations. The oocytes destroyed cannot be replaced because oogonia do not persist after birth.