In vitro approaches for predicting drug-drug interactions (DDIs) caused by alterations in transporter protein regulation are not well established. However, reports of transporter regulation via nuclear receptor (NR) modulation by drugs are increasing. This study examined alterations in transporter protein levels in sandwich-cultured human hepatocytes (SCHH; n = 3 donors) measured by liquid chromatography–tandem mass spectrometry–based proteomic analysis after treatment with N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-(2,2,2-trifluoroethyl)benzenesulfonamide (T0901317), the first described synthetic liver X receptor agonist. T0901317 treatment (10 μM, 48 hours) decreased the levels of organic cation transporter (OCT) 1 (0.22-, 0.43-, and 0.71-fold of control) and organic anion transporter (OAT) 2 (0.38-, 0.38-, and 0.53-fold of control) and increased multidrug resistance protein (MDR) 1 (1.37-, 1.48-, and 1.59-fold of control). The induction of NR downstream gene expression supports the hypothesis that T0901317 off-target effects on farnesoid X receptor and pregnane X receptor activation are responsible for the unexpected changes in OCT1, OAT2, and MDR1. Uptake of the OCT1 substrate metformin in SCHH was decreased by T0901317 treatment. Effects of decreased OCT1 levels on metformin were simulated using a physiologically-based pharmacokinetic (PBPK) model. Simulations showed a clear decrease in metformin hepatic exposure resulting in a decreased pharmacodynamic effect. This DDI would not be predicted by the modest changes in simulated metformin plasma concentrations. Altogether, the current study demonstrated that an approach combining SCHH, proteomic analysis, and PBPK modeling is useful for revealing tissue concentration–based DDIs caused by unexpected regulation of hepatic transporters by NR modulators.

Organic anion transporter 1 (OAT1), expressed at the basolateral membrane of renal proximal tubule epithelial cells, mediates the renal excretion of many clinically important drugs. Previous study in our laboratory demonstrated that ubiquitin conjugation to OAT1 leads to OAT1 internalization from the cell surface and subsequent degradation. The current study showed that the ubiquitinated OAT1 accumulated in the presence of the proteasomal inhibitors MG132 and ALLN rather than the lysosomal inhibitors leupeptin and pepstatin A, suggesting that ubiquitinated OAT1 degrades through proteasomes. Anticancer drugs bortezomib and carfilzomib target the ubiquitin-proteasome pathway. We therefore investigate the roles of bortezomib and carfilzomib in reversing the ubiquitination-induced downregulation of OAT1 expression and transport activity. We showed that bortezomib and carfilzomib extremely increased the ubiquitinated OAT1, which correlated well with an enhanced OAT1-mediated transport of p-aminohippuric acid and an enhanced OAT1 surface expression. The augmented OAT1 expression and transport activity after the treatment with bortezomib and carfilzomib resulted from a reduced rate of OAT1 degradation. Consistent with this, we found decreased 20S proteasomal activity in cells that were exposed to bortezomib and carfilzomib. In conclusion, this study identified the pathway in which ubiquitinated OAT1 degrades and unveiled a novel role of anticancer drugs bortezomib and carfilzomib in their regulation of OAT1 expression and transport activity.

The solute carrier family 16 (SLC16) is comprised of 14 members of the monocarboxylate transporter (MCT) family that play an essential role in the transport of important cell nutrients and for cellular metabolism and pH regulation. MCTs 1–4 have been extensively studied and are involved in the proton-dependent transport of L-lactate, pyruvate, short-chain fatty acids, and monocarboxylate drugs in a wide variety of tissues. MCTs 1 and 4 are overexpressed in a number of cancers, and current investigations have focused on transporter inhibition as a novel therapeutic strategy in cancers. MCT1 has also been used in strategies aimed at enhancing drug absorption due to its high expression in the intestine. Other MCT isoforms are less well characterized, but ongoing studies indicate that MCT6 transports xenobiotics such as bumetanide, nateglinide, and probenecid, whereas MCT7 has been characterized as a transporter of ketone bodies. MCT8 and MCT10 transport thyroid hormones, and recently, MCT9 has been characterized as a carnitine efflux transporter and MCT12 as a creatine transporter. Expressed at the blood brain barrier, MCT8 mutations have been associated with an X-linked intellectual disability, known as Allan-Herndon-Dudley syndrome. Many MCT isoforms are associated with hormone, lipid, and glucose homeostasis, and recent research has focused on their potential roles in disease, with MCTs representing promising novel therapeutic targets. This review will provide a summary of the current literature focusing on the characterization, function, and regulation of the MCT family isoforms and on their roles in drug disposition and in health and disease.

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A "kind and thoughtful" British Transport Police officer has died after contracting coronavirus.

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Air pollution levels have dropped by more than 40 per cent in a number of UK cities as transport use plummets during the coronavirus lockdown, studies have shown.

An Olympic-style plan to prevent buses and Tube trains getting overcrowded is being drawn up to help London come out of lockdown, it can be revealed today.

France is "very likely" to make face masks compulsory on busy trains and buses, a minister indicated today.

The Scottish Government has recommended wearing face masks in enclosed public spaces like shops and public transport to stop the spread of coronavirus.

The Mayor of London warned against a 'big bang' of lifting lockdown measures

Tottenham manager Jose Mourinho will volunteer to help transport food during the coronavirus pandemic.

Social distancing rules will ‘kill cities’, experts warn – and the future of mass transit hangs in the balance

This is the second feature in our Life after lockdown series, which looks at how Covid-19 could change Australia for good

Before the pandemic struck, Sara Blazey made the same three-hour commute to work, three days a week, for the better part of 12 years. The 63-year-old family lawyer from the Blue Mountains works for a domestic violence legal advice hotline in Parramatta and it used to be that she would wake at 7am, drive seven minutes to Hazelbrook station and from there catch the 7.17am train to Parramatta before making the same one-and-a-half hour trip home in the evening.

With the pandemic, all that would change. Domestic violence support services such as the one Blazey worked for were declared “essential” services, meaning they could keep operating despite restrictions. To ensure they could do so safely, the organisation did what some commentators long thought impossible and began to transition its employees into working from home.

A leading international transportation strategist says Sydney can never have a world-class public transport system, despite the NSW Government's record investment in major projects.

NSW Transport Minister Andrew Constance wants to follow London's lead and take "drastic action" by ditching diesel and renewing Sydney's 8,000 bus fleet.

Photosynthetic systems in nature transport energy very efficiently towards a reaction center, where it is converted into a useful form for the organism. Scientists have been using this as inspiration to learn how to transport energy efficiently in, for example, molecular electronics. Physicist Richard Hildner from the University of Groningen and colleagues have investigated energy transport in an artificial system made from nanofibres. The results were published in the Journal of the American Chemical Society.

The Secretary of State will be joined at Downing Street with deputy chief medical officer Professor Jonathan Van-Tam.

Jorge Flores-Rojas, 44, an undocumented Mexican national, was sentenced to 24 years in prison by Chief Judge Robert J. Conrad, Jr. in Charlotte, N.C., for two counts of sex trafficking of minors and one count of interstate transportation of an adult for purposes of commercial sex. Flores-Rojas pled guilty to the charges on Oct. 7, 2008.

Robert P. Merz, 45, was convicted by a federal jury in Philadelphia today of advertising, transporting, receiving and possessing child pornography.

The Department announced that it has moved to intervene in a lawsuit filed in federal court in Jackson, Miss., challenging inaccessibility in Jackson’s public transportation system. The pending lawsuit, filed by 11 residents of Jackson with disabilities and two non-profit organizations that work on behalf of people with disabilities, alleges violations of the Americans with Disabilities Act and the Rehabilitation Act of 1973 (ADA).

William Travis Brown, 39, of Sellersburg, Ind., was convicted today by a federal jury in Indianapolis of transporting and possessing child pornography. Brown was charged on July 8, 2009, in an amended indictment with one count of transportation and one count of possession of child pornography.

The Department will not challenge a proposal by seven regional less-than-truckload (LTL) freight transportation companies to bid jointly and engage in other collaborative activity as part of their nationwide LTL truck transportation services joint venture.

Robert P. Merz was sentenced to life in prison today for advertising, transporting, receiving and possessing child pornography.

Michael Wildridge, 41, pleaded guilty today to transportation and possession of child pornography and was sentenced to 10 years in prison.

A federal jury in Indianapolis convicted William Travis Brown on July 23, 2009, of one count of transportation and one count of possession of child pornography.

Mack Gordon Harris Sr., 67, of Social Circle, Ga., pleaded guilty today to transporting a minor for illegal sexual activity.

Clement Calhoun, a member of the Cherokee Nation in North Carolina, was sentenced in federal court in the Western District of North Carolina, to six months in prison for illegally transporting and selling 51 bear gall bladders.

Mack Gordon Harris Sr., 67, was sentenced today to 121 months in prison for transporting a minor for illegal sexual activity.

The United States has reached a comprehensive settlement agreement with the city of Jackson, Miss., to improve access to public transportation for individuals with disabilities.

The Alaska Department of Transportation and Public Facilities has agreed to pay nearly $1 million to resolve allegations that it violated the Clean Water Act at numerous sites in Alaska

In response to a federal enforcement action for excessive train engine idling, the Massachusetts Bay Transportation Authority (MBTA) and the Massachusetts Bay Commuter Railroad Company (MBCR) will spend more than $2 million to reduce diesel locomotive emissions throughout the MBTA’s commuter rail system.

Jeffrey Robert Libman, the vice president and co-director of Webe Web Corporation, a Florida corporation, pleaded guilty today to 16 counts of transporting child pornography, announced Assistant Attorney General Lanny A. Breuer of the Criminal Division and U.S. Attorney Joyce White Vance of the Northern District of Alabama.

Jeffrey Robert Libman, the vice president and co-director of Webe Web Corporation, a Florida corporation, was sentenced yesterday to 108 months in prison for transporting child pornography.

The Department of Justice announced today that it has resolved claims made by Stephen Ralston against the South Bend, Ind., Public Transportation Corporation (TRANSPO) under the Uniformed Services Employment and Reemployment Rights Act of 1994.

The Department of Justice today filed a lawsuit on behalf of Dave Axtell, a U.S. Air Force reservist, against James J. Williams Bulk Service Transport Inc., its parent company Trans-System Inc., and another Trans-System subsidiary, System TWT Transportation Inc.

Leonard Wasylyk, 49, pleaded guilty before U.S. District Judge Sue L. Robinson in the District of Delaware.

According to his plea agreement, from approximately December 2006 through August 2008, Terry Lee Nolley, 47, and others conspired to operate “Country Lounge,” a secure web-based bulletin board dedicated to trading images of child pornography.

Wright Brothers Construction Co., of Charleston, Tenn., and the Georgia Department of Transportation (GDOT) have agreed to pay a $1.5 million penalty and spend more than $1.3 million to offset environmental damages to resolve alleged violations of the Clean Water Act.

Leonard Wasylyk, 49, was also sentenced to lifetime supervised release and will be required to register as a sex offender in any jurisdiction in which he lives, works or attends school.

Charles Kizer, 53, from Memphis, Tenn., was sentenced late Friday by U.S. District Judge Samuel H. Mays, Jr. to 10 years in prison for violating the Mann Act.

Anthony Mangione, 51, of Parkland, Fla., pleaded guilty today to one count of transportation of child pornography.

Anthony Mangione, 52, of Parkland, Fla., was sentenced by U.S. District Judge Kenneth A. Marra in West Palm Beach, Fla.

Bryan Benson, a former Anderson, Calif., police officer, was arrested today on charges of deprivation of civil rights for sexually assaulting a woman while transporting her to jail and of trying to conceal his criminal conduct, announced the Justice Department.

Montell Williams, of Chicago, pleaded guilty today in Hammond, Ind., to violating the Mann Act by transporting a woman across state lines for the purpose of having her engage in prostitution.

Two former employees at the Marine Corps Logistics Base Albany (MCLB-Albany) have pleaded guilty to receiving bribes related to a scheme to funnel freight hauling business to a local transportation company resulting in the loss of millions of dollars to the United States government.