Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois, Urbana, 61801.
The glucosinolate hydrolysis product 1-isothiocyanato-3-(methylsulfinyl)-propane (IMSP), also known as iberin, is consumed in the average human (US) diet at approximately 1 mumol/kg/day. The chemoprotective effects observed with the consumption of cruciferous vegetables may be due to the presence of specific glucosinolate hydrolysis products either within the crucifers, or formed after ingestion of the crucifers. The mechanism of chemoprotection may be through selective induction of components of Phase II xenobiotic metabolizing enzymes. The influence of repeated administration of low concentrations of IMSP by gavage on components of Phase I and Phase II xenobiotic metabolizing systems was examined in the liver and small intestine of male Fischer 344 rats. Doses of 1, 10 and 100 mumol IMSP/kg, administered by gavage for 7 days, did not alter weight gain, or hepatic and renal weights, relative to body weight, and did not cause any histological lesions. Intestinal glutathione S-transferase (GST) activity and NAD(P)H:quinone reductase (QR) activities were significantly elevated to 3.1 and 8.1 times control values, respectively, at the 100 mumol/kg dose only. The administration of IMSP at 1, 10 or 100 mumol/kg had no significant effect on hepatic Phase I enzymes activities (cytochrome P-450 concentrations, ethoxycoumarin O-deethylase [ECD] and aminopyrine N-demethylase [AND] activities) or Phase II enzyme activities (GST, QR and UDP-glucuronosyltransferase [UDP-GT] activities towards 1-naphthol or 4-hydroxybiphenyl), at any of the doses tested and no effect on intestinal enzyme activities at doses below 100 mumol IMSP/kg. It is concluded that IMSP does not have a significant influence on induction of the Phase I or Phase II xenobiotic metabolizing enzymes in rats when tested at doses approximating those found in the human diet.
Department of Enviornmental Health Sciences, Division of Toxicological Sciences, Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD 21205.
Stromal cells from DBA/2 mouse bone marrow have been shown to be susceptible to cytotoxicity induced by several redox-active metabolites of benzene, including hydroquinone (HQ). Treatment with HQ also alters the composition of stromal cell populations by preferentially killing stromal macrophages compared to stromal fibroblasts. This cytotoxicity can be prevented by 1,2-dithiole-3-thione (DTT) as a result of the induction of quinone reductase (QR), a quinone-processing enzyme, and glutathione. The inductive activities of DTT protected stromal cells against HQ-induced cytotoxicity and against HQ-induced impairment of stromal cell ability to support myelopoiesis. In vivo feeding of DTT to DBA/2 mice increased QR activity within the bone marrow compartment and protected bone marrow stromal cells isolated from the DTT-fed animals from ex vivo HQ challenge. Thus, the inducibility of cellular defense mechanisms and xenobiotic-processing enzymes by chemoprotective agents such as DTT may be a useful strategy for protecting against chemically induced bone marrow toxicities.
Department of Medicine, Northwestern University Medical School, Chicago, IL 60611.
Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione; RP 35972] is a synthetic, substituted 1,2-dithiole-3-thione previously used in humans as an antischistosomal agent. Cruciferous vegetables (e.g., Brussels sprouts, cabbage) contain several agents, including dithiolethiones, which appear to inhibit carcinogenesis; however, it is unclear which dietary compounds produce the protective effects. Animal studies have demonstrated that oltipraz is a potent inducer of Phase II detoxification enzymes, most notably glutathione-S-transferase (GST). Laboratory evaluations have shown that dietary concentrations of oltipraz produce marked inhibition of aflatoxin B1-induced hepatic tumorigenesis in rats. Levels of hepatic aflatoxin-DNA adducts, urinary aflatoxin-N7-guanine, and serum aflatoxin-albumin adducts decreased when biliary elimination of aflatoxin-glutathione conjugants increased, thus providing predictive biomarkers that measured a chemopreventive effect. In other animal experiments, oltipraz was found to inhibit chemically induced carcinogenesis in bladder, colon, breast, stomach, and skin cancer models. In addition, oltipraz has been shown to be non-mutagenic, a radioprotector, and a chemoprotective agent against carbon tetrachloride and acetaminophen toxicity. More recent studies in rats suggest that unsubstituted 1,2-dithiole-3-thiones may more effectively inhibit aflatoxin-induced hepatic tumorigenesis and induce electrophile detoxification enzymes. Multiple human clinical trials have been conducted using 1.0-4.5 gram doses of oltipraz over 1-3 days for the treatment of schistosomiasis. Phototoxicity has precluded its use in tropical areas. More recently, a 6 month Phase I trial was completed in which patients with resected colon polyps, or females with first degree relatives with breast cancer, were given oral daily doses of oltipraz at 125 mg or 250 mg. The maximum tolerated dose of oltipraz was < or = 125 mg daily. Grade I/II toxicities included photosensitivity/heat intolerance, GI and neurologic toxicity. Peak plasma concentrations were analyzed by HPLC with wide variability. In another Phase I study, a single oral dose of oltipraz was given to normal volunteers at dose levels of 125, 250, 375, and 500 mg. There was no significant difference in half-life (t1/2) between the four dose levels nor in clearance at the 125 and 250 mg levels. Peak oltipraz levels > or = 1.0 microgram/mL were achievable with marked interpatient variability. A series of small trials evaluating single oral doses of oltipraz for up to 28 days (dosing range 1 mg/kg-3 mg/kg/day) also showed a short t1/2 (4.1-5.3 hours), a sustained steady state without variation after a loading dose, and increased serum and urine concentrations with consumption of a high-fat diet.
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Cisplatin is an active cytostatic that became successful in the treatment of several types of solid tumours after its nephrotoxic potential was controlled by hydration and diuresis. Thiol compounds were tested to reduce further cisplatin-induced nephrotoxicity. Thiosulphate is rapidly excreted by the kidneys and protects against cisplatin-induced nephrotoxicity by inactivating reactive platinum species in the kidney. Due to inactivation of cisplatin in the circulation, thiosulphate also interferes with its antitumour activity. Therefore, it is mainly used in two-route schedules, whereby cisplatin is delivered locally to the tumour (i.p. or i.a.) while systemic (i.v.) thiosulphate protects the kidneys. Diethyldithiocarbamate was shown to protect against cisplatin-induced nephrotoxicity in several animal models by reversing cellular damage. However, in the clinic it has been less successful, partly due to its central nervous system toxicity. The endogenous thiol compounds glutathione and metallothionein have been shown to reduce cisplatin-induced toxicity both in animal models and in clinical trials. However, the results are rather preliminary and a reduction in therapeutic efficacy may be expected, for both glutathione and metallothionein have been reported to be involved in platinum resistance. The thioether methionine has been shown to reduce cisplatin-induced nephrotoxicity in animal models but it has not yet been tested in the clinic. Cisplatin-induced acute emesis can be sufficiently controlled with a new class of 5-hydroxytryptamine-3 (5HT3)-receptor blockers, but delayed emesis remains a problem. High-dose cisplatin regimens with protection of the kidneys induces ototoxicity, peripheral neuropathy and myelotoxicity, which become dose-limiting. Neurotoxicity was partly reversed by the neurogenerative agent ORG2766, but this agent does not reduce other cisplatin-induced toxicities. Therefore, an agent capable of protecting multiple non-tumour tissues is needed. Carboplatin is a second-generation analogue of cisplatin with less nephro-, neuro- and ototoxicity. Carboplatin is at least as active as cisplatin at its maximum tolerated dose, which is defined by its myelotoxicity. Protection from carboplatin-induced myelotoxicity may be controlled by autologous bone marrow transplantation and/or hematopoietic growth factor infusions. High-dose carboplatin schedules may cause nephrotoxicity, neurotoxicity and ototoxicity. Again, the protection of multiple non-tumour tissues is needed. WR2721 appears to be such a modulating agent capable of protecting multiple non-tumour tissues. It was shown to be preferentially metabolized and taken up as the thiol metabolite WR1065 by non-tumour tissues as compared with (hypoxic) solid tumours. It was shown to protect mice from cisplatin-induced nephrotoxicity and from cisplatin- and carboplatin-induced myelotoxicity without interfering with the antitumour activity.