J. Christopher Gorski

The major concerns with endocrine disruptors in the environment are based mostly on effects that have been observed on the developing embryo and fetus. The focus of the present manuscript is on disruption of three hormonal systems: estrogens, androgens, and thyroid hormones. These three hormonal systems have been well characterized with regard to their roles in normal development, and their actions during development are known to be perturbed by endocrine-disrupting chemicals. During development, organs are especially sensitive to low concentrations of the sex steroids and thyroid hormones. Changes induced by exposure to these hormones during development are often irreversible, in contrast with the reversible changes induced by transient hormone exposure in the adult. Although it is known that there are differences in embryonic/fetal/neonatal versus adult endocrine responses, minimal experimental information is available to aid in characterizing the risk of endocrine disruptors with regard to a number of issues. Issues discussed here include the hypothesis of greater sensitivity of embryos/fetuses to endocrine disruptors, irreversible consequences of exposure before maturation of homeostatic systems and during periods of genetic imprinting, and quantitative information related to the shape of the dose-response curve for specific developmental phenomena.

AIMS: Cytochrome P450 2E1 (CYP2E1) is thought to activate a number of protoxins, and has been implicated in the development of liver disease. Increased hepatic expression of CYP2E1 occurs in rat models of diabetes but it is unclear whether human diabetics display a similar up-regulation. This study was designed to test the hypothesis that human diabetics experience enhanced CYP2E1 expression. METHODS: The pharmacokinetics of a single dose of chlorzoxazone (500 mg), used as an index of hepatic CYP2E1 activity, was determined in healthy subjects (n = 10), volunteers with Type I (n = 13), and Type II (n = 8) diabetes mellitus. Chlorzoxazone and 6-hydroxychlorzoxazone in serum and urine were analysed by high-performance liquid chromatography. The expression of CYP2E1 mRNA in peripheral blood mononuclear cells was quantified by reverse transcriptase-polymerase chain reaction. RESULTS: The mean +/- s.d. (90% confidence interval of the difference) chlorzoxazone area under the plasma concentration-time curve was significantly (P </= 0.05) reduced in obese Type II diabetics (15.7 +/- 11.3 micro g h ml-1; 9, 22) compared with healthy subjects (43.5 +/- 16.9 micro g h ml-1; 16, 40) and Type I diabetics (32.8 +/- 9.2 micro g h ml-1; 9, 25). There was a significant two-fold increase in the oral clearance of chlorzoxazone in obese Type II diabetics compared with healthy volunteers and Type I diabetics. The protein binding of chlorzoxazone was not significantly different between the three groups. In contrast, Type 1 diabetics and healthy volunteers demonstrated no difference in the oral clearance of chlorzoxazone. The urinary recovery of 6-hydroxychlorzoxazone as a percentage of the administered dose was not different between healthy, Type I and obese Type II diabetics. The elimination half-life of chlorzoxazone did not differ between the three groups. CYP2E1 mRNA was significantly elevated in Type I and obese Type II diabetics compared with healthy volunteers. The oral clearance of chlorzoxazone, elimination half-life, Tmax, and Cmax were not significantly influenced by weight, body mass index, serum glucose, serum cholesterol, or glycosylated haemoglobin. CONCLUSIONS: There was a marked increase in hepatic CYP2E1 activity in obese Type II diabetics as assessed by chlorzoxazone disposition. Increased expression of CYP2E1 mRNA in peripheral blood mononuclear cells was found in both types of diabetes mellitus. Adverse hepatic events associated with Type II diabetes may be in part a result of enhanced CYP2E1 expression and activity.

Background St John's wort (Hypericum perforatum) is a popular over‐the‐counter dietary supplement and herbal remedy that has been implicated in drug interactions with substrates of several cytochrome P450 (CYP) isozymes. The effect of St John's wort on CYP activity in vivo was examined with a probe drug cocktail. Methods Twelve healthy subjects (5 female, 7 male) completed this 3‐period, open‐label, fixed schedule study. Tolbutamide (CYP2C9), caffeine (CYP1A2), dextromethorphan (CYP2D6), oral midazolam (intestinal wall and hepatic CYP3A), and intravenous midazolam (hepatic CYP3A) were administered before, with short‐term St John's wort dosing (900 mg), and after 2 weeks of intake (300 mg 3 times a day) to determine CYP activities. Results Short‐term administration of St John's wort had no effect on CYP activities. Long‐term St John's wort administration caused a significant ( P &lt; .05) increase in oral clearance of midazolam from 121.8 ±70.7 to 254.5 ±127.8 and a corresponding significant decline in oral bioavailability from 0.28 ±0.15 to 0.17 ±0.06. In contrast to the &gt;50% decrease in the area under the plasma concentration‐time curve (AUC) when midazolam was administered orally, long‐term St John's wort administration caused a 20% decrease in AUC when midazolam was given intravenously. There was no change in CYP1A2, CYP2C9, or CYP2D6 activities as a result of St John's wort administration. Conclusion Long‐term St John's wort administration resulted in a significant and selective induction of CYP3A activity in the intestinal wall. St John's wort did not alter the CYP2C9, CYP1A2, or CYP2D6 activities. Reduced therapeutic efficacy of drugs metabolized by CYP3A should be anticipated during long‐term administration of St John's wort. Clinical Pharmacology &amp; Therapeutics (2001) 70 , 317–326; doi: 10.1016/S0009‐9236(01)00127‐8