Creatine glycine anil glucose Oguri et al 1998 Cooked chicken was found to contain 18 21 jxg PhIP per 200 g serving Rulpe a 2000

Intakes of PhIP have been estimated to range from nanograms to tens of micrograms per day, depending on flesh food consumption and preparation methods (Lavton et al.. 1995).

Digestion and absorption

The site, mechanism, and effectiveness of HA uptake from the intestinal lumen is incompletely understood. More is known about several transporters that pump ItAs back into the lumen, some of it from circulating blood. At equal concentrations the basolateral to apical efflux is several-fold greater than the apical to basolateral influx (Walle and Walle, 1999), The ABC transporter MRP I (multidrug resistance protein I) pumps its substrates across the basolateral lumen into the entcrocyte (Walle and Walle, 1999), P-glvcoprotein, the product of the MDR-1 gene (Walle and Walle. 1999; HofTmeyer el al.. 2000), MRP2 (Walgren et al.. 2000). and possibly MRP3. pump HAs (and many other xenobiotic compounds) across the apical entcrocyte membrane into the intestinal lumen.

Metabolism

Metabolism of xenobiotics often involves two types of metabolic processes, mainly in the liver, to a lesser extent in kidney and other organs.

The iirst. activating reactions, are referred to as phase I reactions. Phase I reactions most often involve hydroxylation or oxidation of the compound; a variety of other reactions are also possible. The second type, the phase II reactions, include conjugating and other modify ing reactions. These molecular modifications tend to make the original compound more polar and enhance their renal excretion. Phase 1 reactions often increase the reactivity of xenobiotics towards DNA and proteins. Phase II enzymes, on the other hand, tend to decrease the potential for harm by speeding up their elimination. I iowever. this is not universally the ease. Since phase I enzymes activities are a prerequisite for phase II-dependent modification the concerted and balanced action of members from both classes minimize risk. What is more, some phase Il-catalyzcd reactions (e.g. sulfotransferase-catalyzcd generation of highly reactive N-sulfonyloxy HA derivatives) actually increase the potential for harm. Many of the enzymes that catalyze either phase I or phase II enzymes vary greatly in their activity due to differences in genetic makeup, gender, age. or exposure to these or other compounds (Williams. 2001).

Phase I reactions: The initial step of HA metabolism, as of most xenobiotics, usually occurs in the liver and is mainly hydroxylation by microsomal cytochrome P450 isoenzyme I A2(CYP1 A2; TCI, 14.14.1). In peripheral tissues the isoenzymes CYPIA1 and CYPI HI catalyze the same reaction ((.iooderham el al., 2001>. Reactions catalyzed by epoxide hydrolases (EC3.3.2J, microsomal and cytosolic isoenzymes), numerous peroxidases, and other enzymes may contribute to a lesser degree in liver, small intestines

Especially genotoxic metabolites

Readily excreted metabolites

N;-suflonyloxy PhIP

N2-hydroxy PhIP N^-glucuronide

SULT1A2, SULT1A3

UGT1A1

UGT1A9

N^-ftydroxy PhIP N-'-glucuronide H

OH OH

N?-hydroxy PhIP

CYP1A1 (TBI) extrahepauc CYP1A2 hepatic

PhIP N -glucuronide

NAOH-depends n i reductase

DGT1A1

NATS

UGT1A9

PhIP N3-glucuronide H

CYP1A1 (1B1> extrahepatic CYP1A2 hepatic

SULT1A1

4'-sulfonyloxy PhIP

4 -hydroxy PhIP

4'-hydroxy PhIP glucuiomde

N;'-acetoxy PhIP

NJ-Giutamionyi-N:-acetoxy PhIP ch HOOC — C—N—C—C-

Figur* S.3 Metabolism of PhIP

or other tissues ( Williams and Phillips. 2000). The main hydroxylalion product is N2-hydroxy-PhlP. Ring-hydroxylated products also arise (Buonarati et «/., 1992). but much less are produced in humans than in rodents. C'YPl A2. CYP1 Al, and CYPI B1 are inducible by various xenobioties including poly eye lie aromatic hydrocarbons (PAlis), dioxins. and polychlonnated biphenyls (PCBs). Their expression is inhibited by some isothiocyanatcs. including sulforaphane from broccoli (I-isothiocyanaie-4-methylsullinylbutane) and beta-phenylethyl isothiocyanate(PEITC) from watercress. Phase II reactions: Several UDP-gIucuronosyltransferases (UGT) in the liver, less in other tissues, can conjugate HAs, The isoenzyme UGT1A1 conjugates preferentially at N2. UGTIA9 preferentially at N3 (Malfatti and Feltou, 2001). Overall, the predominant product is N2-hydroxy glucuronide (Gooderham et al.. 2001). Conjugation also occurs at N2 (without prior hydroxylation). N3, and at hydroxy groups of the phenyl nng. Glueuronides can be excreted into bile. N3-glucuronides. but not N2-glucuronides, can then be cleaved by bacterial beta-glucuronidases in the large intestine (Gooderbam et al.. 2001).

The sulfotransfcrases SULT1A2, SULT1A3 (phenol-sulfating phenol sulfotrans-ferase 1; EC2.8.2.1) in the liver, and SULT1FI in mammary tissue can activate N-hydroxvlated PhIP (Williams, 2001). SULT1FI is inducible by progesterone. Since N-sulfonyloxy derivatives of II As are highly reactive, their metabolic endpoint tends to be the formation of adducts with DNA and other macromotecules(see below).

Arylamine N-acety I transferases (NAT; EC2.3.1.5) are another group of enzymes that rapidly metabolize hydroxylated HAs and thereby make them more reactive. Fast NAT2 acetylators produce more HA/DNA adducts than slow acetylators (Calabrese. 1996).

Reduced glutathione can be conjugated with some HAs. Such reactions are catalyzed by a family of microsomal glutathione S-transferases (GST: EC2.5.1.I8) with broad specificity (van Bladeren. 2000). In the ease of PhIP, only N-acetoxy-PhIP can form such a conjugate, catalyzed by the isoenzyme GST At-!: the other isoenzymes are either little or not at all reactive (Coles el al.. 2001). Conjugation of PhIP lo glutathione makes it less likely to bind to DNA (Nelson etal., 2001) and promotes its transport (mediated by MRP2 and other transporters) out of cells (Dietrich et al., 2001) and its excretion with urine. An additional detoxification pathway is the NADH-dependent reduction of N2-hydroxy-PhIP to its amine (king et al.. 1999).

Many phase II enzymes are inducible by food constituents including thiocyanates (in broccoli, water cress, and other Hrassiea species), flavonoids, and polyphenols (Wilkinson and Clapper. 1997).

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