Topical application of coal tar (U.S.P.) to neonatal rats resulted in the induction of hepatic cytosolic glutathione-S-transferase and microsomal epoxide hydrolase and aminopyrine N-demethylase activities. Analogous to the effect of the polychlorinated biphenyl Aroclor 1254, treatment of neonatal rats with coal tar resulted in a one nm shift to the blue region in the wavelength maximum of the hepatic microsomal hemoprotein cytochrome P-450. These results demonstrate that therapeutic coal tar contains both type I and type II inducers of hepatic drug-metabolizing enzymes.

Animals↗

PubMed1982

The effect of psoralens on hepatic and cutaneous drug metabolizing enzymes and cytochrome P-450.

Psoralens are tricyclic furocoumarins with potent photosensitizing properties in the skin and are now widely used in the treatment of several dermatologic diseases. In this study the effect of 3 different psoralens 8-methoxypsoralen (8-MOP), 4,5',8-trimethylpsoralen (TMP) and isopsoralen on hepatic microsomal drug-metabolizing enzymes and cytochrome P-450 has been assessed in mice and rats. 8-MOP administered orally to CD-1 mice daily for 6 days caused 2-3 fold increases in hepatic aryl hydrocarbon hydroxylase (AHH), ethylmorphine N-demethylase and cytochrome P-450. The absorbance maximum of the induced cytochrome was at 450 nm. Aniline hydroxylase activity was unchanged. Chronic administration of 8-MOP to hairless mice caused significant enhancement of hepatic ethylmorphine N-demethylase and cytochrome P-450 but had no effect on AHH; whereas chronically administered TMP had no significant effect on any of these parameters. Isopsoralen and TMP administered orally to CD-1 mice daily for 6 days had no effect on any of these liver enzymes or on hepatic P-450. 8-MOP administered daily for 6 days to rats caused a greater than 4-fold enhancement of AHH and greater than 2-fold enhancement of ethylmorphine N-demethylase and cytochrome P-450. These studies indicate that orally administered 8-MOP induces hepatic drug-metabolizing enzymes and cytochrome P-450 to a lesser extent than do the barbituates and suggest that this drug could influence the rate of biotransformation of concomitantly administered drugs in patients undergoing PUVA therapy.

Administration, Oral↗

PubMed1982

Induction of neonatal rat skin and liver aryl hydrocarbon hydroxylase by coal tar and its constituents.

Topical application of coal tar solution (USP) to neonatal rats resulted in the induction of skin and liver aryl hydrocarbon hydroxylase (AHH) activities. Furthermore indirect exposure of the animals to coal tar vapors resulted in induction of the enzyme in skin and liver. Cutaneous application of coal tar to pregnant rats resulted in induction of skin and liver AHH activity in both mothers and prenatal rats. Among several defined constituents of coal tar tested benzo(a)pyrene (BP), anthracene and acridine were found to have measurable induction effects on neonatal rat skin and liver AHH. These studies indicate that therapeutic coal tar solution as well as selected defined chemical constituents of coal tar are capable of altering the activity of AHH in skin and liver.

Acridines↗

PubMed1982

Inhibition of tissue aryl hydrocarbon (benzo[a]pyrene) hydroxylase by 7,8-benzoflavone in birds.

1. Addition of 7,8-benzoflavone (7,8-BF) inhibited both hepatic and renal constitutive activity of aryl hydrocarbon (benzo[a]pyrene) hydroxylase in vitro for a number of avian species. Inhibition of hepatic benzo[a]pyrene hydroxylase was 70-94% in wild pigeon; 46-88% in homing pigeon; 85-93% in house crow; 18-53% in common kite; 56-86% in cattle egret; and for the renal enzyme was 43-84, 52-88, 18-73 and 13-48% respectively. 2. 3-Methylcholanthrene treatment of homing pigeons resulted in the induction of liver and kidney benzo[a]pyrene hydroxylase activity. Induced enzyme activity was also significantly inhibited by 7,8-BF.

Animals↗

PubMed1982

Studies on microsomal cytochrome P-450, monooxygenases and epoxide hydrolase in cultured keratinocytes and intact epidermis from BALB/C mice.

Studies of drug and carcinogen metabolism in cultured keratinocytes and in intact epidermis from the skin of BALB/C mice were performed. The cultured cells were shown to retain 33 to 40% of corresponding intact epidermal aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin-O-de-ethylase (7-ED) and epoxide hydrolase activities. In vitro treatment of the cells or in vivo application to the skin of animals with the polycyclic aromatic hydrocarbons benz(a)anthracene (BA) or benzo(a)pyrene resulted in significant induction of AHH and 7-ED activities. The responsiveness of AHH was greater than that of 7-ED in both preparations. BA (4 x 10(-4) M) induced AHH and 7-ED at least 12- and 4-fold, respectively, in either the keratinocytes or intact epidermis, whereas epoxide hydrolase activity was not altered in either preparation. All of these enzyme activities were predominantly located in the microsomal fraction of the keratinocytes and the epidermis. Keratinocyte AHH had a pH optimum at 7.4. The apparent Km for benzo(a)pyrene as substrate in control and BA-induced cells was 10 and 6 microM, respectively, whereas Vmax was 15-fold greater in the carcinogen-treated cells. CO-difference spectra demonstrated the presence of the heme-protein cytochrome P-450 in microsomes prepared from keratinocytes and intact epidermis; absorption maximum was between 451 to 453 nm. The metabolic activity of keratinocytes was further demonstrated in the Ames mutagen assay. A supernatant (9000 x g) prepared from keratinocytes pretreated with BA enhanced the mutagenesis of 2-aminoanthracene in the TA98 strain of Salmonella typhimurium. These studies indicate that cultured keratinocytes provide a useful experimental model system for the study of epidermal drug and carcinogen metabolism.

Animals↗

PubMed1982