Michael J. Finnen

Aryl hydrocarbon hydroxylase activity and psoriasis

Aryl hydrocarbon hydroxylase (AHH) has been measured in the skin, jejunum and liver of normal and psoriatic individuals. We have been unable to confirm previous reports of an abnormality in AHH activity in patients with psoriasis. Re-examination of the laboratory records on which the original reports were based leads us to doubt their veracity and validity.

Differential regulation of early phase and late phase responses in human neutrophils by cAMP

The elevation of intracellular levels of cyclic AMP by forskolin stimulation of adenylate cyclase regulates early and late phase neutrophil responses differentially. Early phase neutrophil responses as measured by shape change in response to chemotactic factors, transmigration across a polycarbonate membrane and priming were unaffected by forskolin-induced elevation of intracellular cAMP. Late phase neutrophil responses such as release of superoxide anions, activation of phospholipase A2 and platelet activating factor (PAF) synthesis were inhibited by increasing intracellular cAMP through the addition of 10 microM forskolin for 10 min prior to stimulation. N-Formyl-methionyl-leucyl-phenylalanine-stimulated arachidonic acid release fell from 9.3% (untreated cells) to 4.6% in forskolin-treated cells. PAF generation was also inhibited from 430 pg/10(6) cells in untreated cells to background levels in forskolin-treated cells (110 pg/10(6) cells). Also, the reduction of cytochrome c by superoxide anions fell from 4.2 nmol/10(6) cells in the absence of forskolin to 2.0 nmol/10(6) cells following forskolin treatment. These results indicate that in neutrophils the elevation of cAMP acts differentially on cellular responses, not affecting early activation events, but markedly inhibiting late events such as the release of inflammatory mediators.

Testicular neonatal imprinting of sex dependent differences in hepatic foreign compound metabolism in the rat.

Abstract A dimethylated chlorocyclodiene epoxide (DME) ∗ is metabolized by adult male rat liver enzymes to produce two g.l.c. detectable metabolites M1 and M2. Liver enzymes from adult female rats metabolize DME producing only metabolite M1 in detectable quantities. This apparent qualitative sex difference in the metabolism of DME is first manifest between the ages of 35 and 45 days. Liver enzymes from rats of both sexes younger than 35 days metabolize DME in a qualitatively similar manner. The actions of the testes in the development of this apparent qualitative sex difference are exerted between the ages of 7 and 14 days. Castration of male rats at and before the age of 7 days results in the expression of a typically feminine pattern of metabolism of DME by liver enzymes in adult life. Castration of male rats after the age of 14 days does not prevent adult liver enzymes from exhibiting a basically masculine pattern of DME metabolism. At ages between 7 and 14 days castration has a graded effect on the metabolism of DME displayed by liver enzymes in adult life. These results suggest that testicular androgens do not play a direct role at puberty and in adulthood in the expression of the ability of liver enzymes to produce metabolite M2, but that the apparent qualitative sex dependent difference in DME metabolism is determined primarily by neonatal imprinting by testicular androgens.

A possible primary role for the pituitary in the control of sex dependent differences in hepatic foreign compound metabolism in the rat

Abstract The role of the pituitary in the control of the neonatally imprinted sex difference in the metabolism of a dimethylated chlorocyclodiene epoxide (DME)∗ was investigated. Hypophysectomy of adult female rats resulted in an effective masculinization of the hepatic metabolism of DME. Adrenalectomy, thyroidectomy, castration or hypophysectomy of adult male rats did not prevent liver enzymes from displaying a basically masculine pattern of DME metabolism. However, castration of male rats at one day old resulted in a basically feminine pattern of metabolism being displayed by liver enzymes in adult life. The effects of adult castration on the metabolism of DME and ethylmorphine by rat liver enzymes were completely reversed by testosterone propionate. The effects of combined hypophysectomy and castration on the hepatic metabolism of these substrates, however, were not reversed by testosterone treatment. These results suggest that sex dependent differences in the metabolism of foreign compounds by adult rat liver enzymes are mediated directly by the pituitary gland.

Effects of Neonatally Administered Chlorpromazine and Reserpine on the Responsiveness of Rat Hepatic Drug-Metabolising Enzymes to Testosterone in Adult Life

The effects of neonatally administered chlorpromazine and reserpine on the response of rat hepatic drug-metabolising enzymes to testosterone in adult life have been investigated using the chlorinated cyclodiene substrate DME. Neonatal treatment with chlorpromazine and reserpine had effects on the metabolism of DME similar to, but not as pronounced as, those of castration when adult. The effects of adult castration of male rats on hepatic microsomal metabolism of DME were fully reversed by treatment with testosterone propionate, with metabolism being restored to that of a control intact male. However, testosterone propionate treatment of either intact or castrated adult males that had received neonatal reserpine or chlorpromazine did not restore levels of metabolism to those characteristic of control adult male rats. These results suggest that neonatally administered chlorpromazine and reserpine alter the sensitivity of hepatic drug-metabolising enzymes to the actions of testosterone in adult life.

Inhibitory effects of centrally acting drugs on the neonatal imprinting of sex differences in the hepatic metabolism of a dimethylated epoxide in the rat

1 The effects of the neonatal administration of reserpine, chlorpromazine, phenobarbitone and morphine on the development of sex differences in hepatic drug metabolism in the rat have been investigated. 2 Treatment of neonatal male rats with reserpine or chlorpromazine for the first two weeks post‐partum significantly inhibited the development of sex differences in drug metabolism in adult life. 3 Similar treatment of neonatal female rats with reserpine or chlorpromazine had no effect on the development of hepatic drug metabolism in adulthood. 4 Morphine or phenobarbitone treatment of neonatal rats of either sex had no effect on the development of sex differences in hepatic drug metabolism in adult life.