The Metabolism Of Dietary Isothiocyanates In Vivo

The first step in the metabolism of dietary or synthetic ITCs involves their conjugation with the nucleophilic sulfhydryl group of glutathione in the mercapturic acid pathway (Fig. 3) (96). After GSH conjugation the resultant ITC conjugates pass through a series of catabolic steps mediated by the enzymes g-glutamyltranspepsidase, cysteinylglycinase, aminopeptidase, and N-acetyltransferase to the final mercapturic acid metabolite excreted in urine, the N-acetylcysteine-S or, alternatively, S-N-(thiocarbomylisothiocyanate)-L-N-acetylcysteine conjugates. Several in vivo studies in A/J mice and rats have identified N-acetylcysteine conjugates of AITC, BITC, sulforaphane, and PEITC in urine, after feeding with either synthetic or plant-derived ITCs (these data are summarized in Table 3). Common to all these studies is the rapid rate at which ITCs are detoxified and excreted in the urine; typically between 30 and 80% of the total ingested ITCs is excreted within 24 hr. Disposition and pharmacokinetic studies using 14C PEITC and 14CPHITC in male Fischer F344 rats addressed the effects of tissue distribution on the excretion of ITCs. High localization of PEITC within the liver, lungs, and blood was observed with 88.7% of the administered dose being excreted in the urine and feces within 48 hr. In contrast, PHITC, a structural analog of PEITC (increased chain length), showed greater retention within the liver, lungs, and blood with only 7% of the dose being excreted in the urine and 47% in feces during 48 hr. The observed retention of PHITC may explain its greater efficacy at inhibiting NNK-induced lung tumor development in rodents. The data also suggest that, unlike PEITC, PHITC may also be metabolized via a different route, as large quantities are eliminated in the feces (105).

Gsts Reaction

Figure 3 Detoxification of isothiocyanates occurs through the mercapturic acid pathway. The initial conjugation reaction mediated by GSTs allows for the subsequent catabolic degradation of S-(N-thiocarbomylisothiocyanate)-L-glu-tathione intermediate to its N-acetylcysteine derivative. NAC conjugates are routinely used for measuring isothiocyanates in urine during epidemiological and/or feeding experiments (see text).

Figure 3 Detoxification of isothiocyanates occurs through the mercapturic acid pathway. The initial conjugation reaction mediated by GSTs allows for the subsequent catabolic degradation of S-(N-thiocarbomylisothiocyanate)-L-glu-tathione intermediate to its N-acetylcysteine derivative. NAC conjugates are routinely used for measuring isothiocyanates in urine during epidemiological and/or feeding experiments (see text).

In humans the principal urinary metabolites of ITCs are the N-acetyl-cysteine derivatives (100,102). Quantification of these has been aided by the development of the 1,2-benzenedithiol derivatization assay developed by Zhang et al. (110). Indeed, this method has often been adopted for use in feeding and epidemiological studies (60,61). In determining the role of myr-osinase in the bioavailability of ITCs several studies have addressed the microbial metabolism of GSLs in humans. Getahun and Chung fed human subjects watercress with active and inactivated myrosinase and measured the urinary excretion of the N-acetylcysteine conjugates in urine (111). Consumption of 150 g of fresh watercress with active myrosinase resulted in the excretion of 17-77% of the administered dose of ITCs in the urine. In contrast, individuals consuming 350 g of watercress with inactivated myrosinase showed a significant reduction to only 7% of the administered dose at 24 hr. In separate experiments these investigators demonstrated the ability of human fecal samples to hydrolyze GSLs to their respective ITCs, with 18% of

TABLE 3 Summary of the Metabolic Studies Conducted Using Dietary-Derived and Synthetic Isothiocyanates In Vivo

Species investigated

Glucosinolate or isothiocyanate studied

Metabolites identified

Site of detection

Ref.

Rat, dog

Rat Rat

Human A/J mice

Human

Human

Fischer F344 rats, B6C3F1 mice Fischer F344 rats

Human

Fischer F344 rats

Human

Human

Human

Human

BITC and its mercapturic acids MITC, EITC,

BTITC, AITC BITC, AITC, MITC, EITC, BTITC BITC from garden cress PEITC

PEITC from watercress AITC from brown mustard AITC

Dose of cauliflower, sinigrin, or AITC PEITC from watercress PEITC and PHITC

Sulforaphane from broccoli Broccoli sprouts containing ITCs Single dose of

PEITC Broccoli sprouts containing ITCs

NAC conjugate

NAC conjugate NAC conjugate

NAC conjugate

4-Hydroxy-4-carboxyl-3-phenylethylthiazolidine-2-thione and NAC conjugate NAC conjugate

NAC conjugate

Rat; NAC conjugate Mouse; -SCN ions

NAC conjugate

NAC conjugate N/D

NAC conjugates NAC conjugate N/D N/D

Urine Feces

Urine

Urine

Urine

Urine Urine

Urine, feces, expired air

Urine Urine

Urine Plasma

Urine and 101

tissues

106 111

Urine, tissues, 105 and expired air

Urine 106

Urine, plasma, 109 serum, erythrocytes

AITC, allyl isothiocyanate; BITC, benzyl isothiocyanate; BTITC, butyl isothiocyanate; EITC, ethyl isothiocyanate; MITC, methyl isothiocyanate; PEITC, phenylethyl isothiocyanate; sinigrin, 2-propenyl glucosinolate.

the total GSLs being degraded with 2 hr. These data implicate colonic bacteria in the bioavailability of ITCs in the human diet. Further investigations by Shapiro et al. also demonstrated that heat inactivation can reduce the levels of ITCs metabolites in urine. In subjects consuming cooked broccoli only 10-20% of the ITCs were excreted compared to those consuming 47% in myrosinase-treated broccoli in which most of the GSLs had been converted to their respective ITCs. Furthermore, removal of colonic bacteria in subjects using antibiotic treatments almost eliminated the detection of these urinary metabolites (107). These data highlight the complex nature of the bioavail-ability of ITCs in the diet with a reliance on both endogeneous plant and microbial myrosinase.

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